Ortho-Condensed Pyridine and Pyrimidine Derivatives (e.g., Purines) as Protein Kinases Inhibitors

ABSTRACT

The invention provides a compound for use as a protein kinase B inhibitor, the compound being a compound of the formula (I) or salts, solvates, tautomers or N-oxides thereof, wherein T is N or CR 5 ; J 1 -J 2  is N═C(R 6 ), (R 7 )C═N, (R 8 )N—C(O), (R 8 ) 2 C—C(O), N═N or (R 7 )C═C(R 6 ); E is a monocyclic carbocyclic or heterocyclic group of 5 or 6 ring members, the heterocyclic group containing up to 3 heteroatoms selected from O, N and S; Q 1  is a bond or a saturated C 1-3  hydrocarbon linker group, one of the carbon atoms in the linker group being optionally be replaced by an oxygen or nitrogen atom, or an adjacent pair of carbon atoms may be replaced by CONR q  or NR q CO where R q  is hydrogen or methyl, or R q  is a C 1-4  alkylene chain linked to R 1  or a carbon atom of Q 1  to form a cyclic moiety; and wherein the carbon atoms of the linker group Q 1  may optionally bear one or more substituents selected from fluorine and hydroxy; Q 2  is a bond or a saturated hydrocarbon linker group containing from 1 to 3 carbon atoms, wherein one of the carbon atoms in the linker group may optionally be replaced by an oxygen or nitrogen atom; and wherein the carbon atoms of the linker group may optionally bear one or more substituents selected from fluorine and hydroxy, provided that the hydroxy group when present is not located at a carbon atom a with respect to the G group; and provided that when E is aryl or heteroaryl, then Q 2  is other than a bond; G is hydrogen, NR 2 R, OH or SH provided that when E is aryl or heteroaryl and Q 2  is a bond, then G is hydrogen; R 1  is hydrogen or an aryl or heteroaryl group, with the proviso that when R 1  is hydrogen and G is NR 2 R 3 , then Q 2  is a bond; and R 2 , R 3 , R 4 , R 6  and R 8  are as defined in the claims.

RELATED APPLICATIONS

This application is related to U.S. provisional patent applications U.S.60/621,821 (filed 25 Oct. 2004) and U.S. 60/684,119 (filed: 24 May2005), the contents of each of which are incorporated herein byreference.

TECHNICAL FIELD

This invention relates to purine, purinone and deazapurine anddeazapurinone compounds that inhibit or modulate the activity of proteinkinase B (PKB) and protein kinase A (PKA), to the use of the compoundsin the treatment or prophylaxis of disease states or conditions mediatedby PKB and PKA, and to novel compounds having PKB and PKA inhibitory ormodulating activity. Also provided are pharmaceutical compositionscontaining the compounds and novel chemical intermediates.

BACKGROUND OF THE INVENTION

Protein kinases constitute a large family of structurally relatedenzymes that are responsible for the control of a wide variety of signaltransduction processes within the cell (Hardie, G. and Hanks, S. (1995)The Protein Kinase Facts Book. I and II, Academic Press, San Diego,Calif.). The kinases may be categorized into families by the substratesthey phosphorylate (e.g., protein-tyrosine, protein-serine/threonine,lipids, etc.). Sequence motifs have been identified that generallycorrespond to each of these kinase families (e.g., Hanks, S. K., Hunter,T., FASEB J, 9:576-596 (1995); Knighton, et al., Science, 253:407-414(1991); Hiles, et al., Cell, 70:419-429 (1992); Kunz, et al., Cell,73:585-596 (1993); Garcia-Bustos, et al., EMBO J., 13:2352-2361 (1994)).

Protein kinases may be characterized by their regulation mechanisms.These mechanisms include, for example, autophosphorylation,transphosphorylation by other kinases, protein-protein interactions,protein-lipid interactions, and protein-polynucleotide interactions. Anindividual protein kinase may be regulated by more than one mechanism.

Kinases regulate many different cell processes including, but notlimited to, proliferation, differentiation, apoptosis, motility,transcription, translation and other signalling processes, by addingphosphate groups to target proteins. These phosphorylation events act asmolecular on/off switches that can modulate or regulate the targetprotein biological function. Phosphorylation of target proteins occursin response to a variety of extracellular signals (hormones,neurotransmitters, growth and differentiation factors, etc.), cell cycleevents, environmental or nutritional stresses, etc. The appropriateprotein kinase functions in signalling pathways to activate orinactivate (either directly or indirectly), for example, a metabolicenzyme, regulatory protein, receptor, cytoskeletal protein, ion channelor pump, or transcription factor. Uncontrolled signalling due todefective control of protein phosphorylation has been implicated in anumber of diseases, including, for example, inflammation, cancer,allergy/asthma, diseases and conditions of the immune system, diseasesand conditions of the central nervous system, and angiogenesis.

Apoptosis or programmed cell death is an important physiological processwhich removes cells no longer required by an organism. The process isimportant in early embryonic growth and development allowing thenon-necrotic controlled breakdown, removal and recovery of cellularcomponents. The removal of cells by apoptosis is also important in themaintenance of chromosomal and genomic integrity of growing cellpopulations. There are several known checkpoints in the cell growthcycle at which DNA damage and genomic integrity are carefully monitored.The response to the detection of anomalies at such checkpoints is toarrest the growth of such cells and initiate repair processes. If thedamage or anomalies cannot be repaired then apoptosis is initiated bythe damaged cell in order to prevent the propagation of faults anderrors. Cancerous cells consistently contain numerous mutations, errorsor rearrangements in their chromosomal DNA. It is widely believed thatthis occurs in part because the majority of tumours have a defect in oneor more of the processes responsible for initiation of the apoptoticprocess. Normal control mechanisms cannot kill the cancerous cells andthe chromosomal or DNA coding errors continue to be propagated. As aconsequence restoring these pro-apoptotic signals or suppressingunregulated survival signals is an attractive means of treating cancer.

The signal transduction pathway containing the enzymesphosphatidylinositol 3-kinase (PI3K), PDK1 and PKB amongst others, haslong been known to mediate increased resistance to apoptosis or survivalresponses in many cells. There is a substantial amount of data toindicate that this pathway is an important survival pathway used by manygrowth factors to suppress apoptosis. The enzymes of the PI3K family areactivated by a range of growth and survival factors e.g. EGF, PDGF andthrough the generation of polyphosphatidylinositols, initiates theactivation of the downstream signalling events including the activity ofthe kinases PDK1 and protein kinase B (PKB) also known as akt. This isalso true in host tissues, e.g. vascular endothelial cells as well asneoplasias. PKB is a protein ser/thr kinase consisting of a kinasedomain together with an N-terminal PH domain and C-terminal regulatorydomain. The enzyme PKB_(alpha) (akt1) itself is phosphorylated on Thr308 by PDK1 and on Ser 473 by a kinase referred to as PDK2, whereasPKB_(beta) (akt2) is phosphorylated on Thr 309 and on Ser 474, andPKB_(gamma) (akt3) is phosphorylated on Thr 305 and on Ser 472.

At least 10 kinases have been suggested to function as a Ser 473 kinaseincluding mitogen-activated protein (MAP) kinase-activated proteinkinase-2 (MK2), integrin-linked kinase (ILK), p38 MAP kinase, proteinkinase Calpha (PKCalpha), PKCbeta, the NIMA-related kinase-6 (NEK6), themammalian target of rapamycin (mTOR), the double-stranded DNA-dependentprotein kinase (DNK-PK), and the ataxia telangiectasia mutated (ATM)gene product. Available data suggest that multiple systems may be usedin cells to regulate the activation of PKB. Full activation of PKBrequires phosphorylation at both sites whilst association between PIP3and the PH domain is required for anchoring of the enzyme to thecytoplasmic face of the lipid membrane providing optimal access tosubstrates.

Activated PKB in turns phosphorylates a range of substrates contributingto the overall survival response. Whilst we cannot be certain that weunderstand all of the factors responsible for mediating the PKBdependent survival response, some important actions are believed to bephosphorylation and inactivation of the pro-apoptotic factor BAD andcaspase 9, phosphorylation of Forkhead transcription factors e.g. FKHRleading to their exclusion from the nucleus, and activation of theNfkappaB pathway by phosphorylation of upstream kinases in the cascade.

In addition to the anti-apoptotic and pro-survival actions of the PKBpathway, the enzyme also plays an important role in promoting cellproliferation. This action is again likely to be mediated via severalactions, some of which are thought to be phosphorylation andinactivation of the cyclin dependent kinase inhibitor ofp21^(CiP1/WAF1), and phosphorylation and activation of mTOR, a kinasecontrolling several aspects of cell size, growth and proteintranslation.

The phosphatase PTEN which dephosphorylates and inactivatespolyphosphatidylinositols is a key tumour suppressor protein whichnormally acts to regulate the PI3K/PKB survival pathway. Thesignificance of the PI3K/PKB pathway in tumourigenesis can be judgedfrom the observation that PTEN is one of the most common targets ofmutation in human tumours, with mutations in this phosphatase havingbeen found in ˜50% or more of melanomas (Guldberg et al 1997, CancerResearch 57, 3660-3663) and advanced prostate cancers (Cairns et al 1997Cancer Research 57, 4997). These observations and others suggest that awide range of tumour types are dependent on the enhanced PKB activityfor growth and survival and would respond therapeutically to appropriateinhibitors of PKB.

There are 3 closely related isoforms of PKB called alpha, beta andgamma, which genetic studies suggest have distinct but overlappingfunctions. Evidence suggests that they can all independently play a rolein cancer. For example PKB beta has been found to be over-expressed oractivated in 10-40% of ovarian and pancreatic cancers (Bellacosa et al1995, Int. J. Cancer 64, 280-285; Cheng et al 1996, PNAS 93, 3636-3641;Yuan et al 2000, Oncogene 19, 2324-2330), PKB alpha is amplified inhuman gastric, prostate and breast cancer (Staal 1987, PNAS 84,5034-5037; Sun et al 2001, Am. J. Pathol. 159, 431-437) and increasedPKB gamma activity has been observed in steroid independent breast andprostate cell lines (Nakatani et al 1999, J. Biol. Chem. 274,21528-21532).

The PKB pathway also functions in the growth and survival of normaltissues and may be regulated during normal physiology to control celland tissue function. Thus disorders associated with undesirableproliferation and survival of normal cells and tissues may also benefittherapeutically from treatment with a PKB inhibitor. Examples of suchdisorders are disorders of immune cells associated with prolongedexpansion and survival of cell population leading to a prolonged or upregulated immune response. For example, T and B lymphocyte response tocognate antigens or growth factors such as interferon gamma activatesthe PI3K/PKB pathway and is responsible for maintaining the survival ofthe antigen specific lymphocyte clones during the immune response. Underconditions in which lymphocytes and other immune cells are responding toinappropriate self or foreign antigens, or in which other abnormalitieslead to prolonged activation, the PKB pathway contributes an importantsurvival signal preventing the normal mechanisms by which the immuneresponse is terminated via apoptosis of the activated cell population.There is a considerable amount of evidence demonstrating the expansionof lymphocyte populations responding to self antigens in autoimmuneconditions such as multiple sclerosis and arthritis. Expansion oflymphocyte populations responding inappropriately to foreign antigens isa feature of another set of conditions such as allergic responses andasthma. In summary inhibition of PKB could provide a beneficialtreatment for immune disorders.

Other examples of inappropriate expansion, growth, proliferation,hyperplasia and survival of normal cells in which PKB may play a roleinclude but are not limited to atherosclerosis, cardiac myopathy andglomerulonephritis.

In addition to the role in cell growth and survival, the PKB pathwayfunctions in the control of glucose metabolism by insulin. Availableevidence from mice deficient in the alpha and beta isoforms of PKBsuggests that this action is mediated by the beta isoform primarily. Asa consequence, modulators of PKB activity may also find utility indiseases in which there is a dysfunction of glucose metabolism andenergy storage such as diabetes, metabolic disease and obesity.

Cyclic AMP-dependent protein kinase (PKA) is a serine/threonine proteinkinase that phosphorylates a wide range of substrates and is involved inthe regulation of many cellular processes including cell growth, celldifferentiation, ion-channel conductivity, gene transcription andsynaptic release of neurotransmitters. In its inactive form, the PKAholoenzyme is a tetramer comprising two regulatory subunits and twocatalytic subunits.

PKA acts as a link between G-protein mediated signal transduction eventsand the cellular processes that they regulate. Binding of a hormoneligand such as glucagon to a transmembrane receptor activates areceptor-coupled G-protein (GTP-binding and hydrolyzing protein). Uponactivation, the alpha subunit of the G protein dissociates and binds toand activates adenylate cyclase, which in turn converts ATP tocyclic-AMP (cAMP). The cAMP thus produced then binds to the regulatorysubunits of PKA leading to dissociation of the associated catalyticsubunits. The catalytic subunits of PKA, which are inactive whenassociated with the regulatory sub-units, become active upondissociation and take part in the phosphorylation of other regulatoryproteins.

For example, the catalytic sub-unit of PKA phosphorylates the kinasePhosphorylase Kinase which is involved in the phosphorylation ofPhosphorylase, the enzyme responsible for breaking down glycogen torelease glucose. PKA is also involved in the regulation of glucoselevels by phosphorylating and deactivating glycogen synthase. Thus,modulators of PKA activity (which modulators may increase or decreasePKA activity) may be useful in the treatment or management of diseasesin which there is a dysfunction of glucose metabolism and energy storagesuch as diabetes, metabolic disease and obesity.

PKA has also been established as an acute inhibitor of T cellactivation. Anndahl et al, have investigated the possible role of PKAtype I in HIV-induced T cell dysfunction on the basis that T cells fromHIV-infected patients have increased levels of cAMP and are moresensitive to inhibition by cAMP analogues than are normal T cells. Fromtheir studies, they concluded that increased activation of PKA type Imay contribute to progressive T cell dysfunction in HIV infection andthat PKA type I may therefore be a potential target for immunomodulatingtherapy.-Aandahl, E. M., Aukrust, P., Skålhegg, B. S., Müller, F.,Frøland, S. S., Hansson, V., Taskén, K. Protein kinase A type Iantagonist restores immune responses of T cells from HIV-infectedpatients. FASEB J. 12, 855-862 (1998).

It has also been recognised that mutations in the regulatory sub-unit ofPKA can lead to hyperactivation in endocrine tissue.

Because of the diversity and importance of PKA as a messenger in cellregulation, abnormal responses of cAMP can lead to a variety of humandiseases derived from this, such as irregular cell growth andproliferation (Stratakis, C. A.; Cho-Chung, Y. S.; Protein Kinase A andhuman diseases. Trends Endrocri. Metab. 2002, 13, 50-52).Over-expression of PKA has been observed in a variety of human cancercells including those from ovarian, breast and colon patients.Inhibition of PKA would therefore be an approach to treatment of cancer(Li, Q.; Zhu, G-D.; Current Topics in Medicinal Chemistry, 2002, 2,939-971).

For a review of the role of PKA in human disease, see for example,Protein Kinase A and Human Disease, Edited by Constantine A. Stratakis,Annals of the New York Academy of Sciences, Volume 968, 2002, ISBN1-57331-412-9.

PRIOR ART

Several classes of compounds have been disclosed as having PKA and PKBinhibitory activity.

For example, a class of isoquinolinyl-sulphonamido-diamines having PKBinhibitory activity is disclosed in WO 01/91754 (Yissum).

WO 93/13072 (Italfarmaco) discloses a class of bis-sulphonamido diaminesas protein kinase inhibitors.

WO 99/65909 (Pfizer) discloses a class of pyrrole[2,3-d]pyrimidinecompounds having protein tyrosine kinase activity and which are ofpotential use as immunosuppressant agents.

WO 2004/074287 (Astra Zeneca) discloses piperazinyl-pyridyl amides foruse in treating autoimmune diseases such as arthritis. The piperazinegroup in the compounds can be linked to a purine group.

WO02/18348 (F. Hoffman La Roche) discloses a class of amino-quinazolinederivatives as alpha-1 adrenergic antagonists. A method for preparingthe amino-quinazoline compounds involves the use of a gem-disubstitutedcyclic amine such as piperidine in which one of the gem substituents isan aminomethyl group.

WO03/088908 (Bristol Myers Squibb) disclosesN-heteroaryl-4,4-disubstituted piperidines as potassium channelinhibitors.

WO01/07050 (Schering) discloses substituted piperidines as nociceptinreceptor ORL-1 agonists for use in treating cough.

US 2003/0139427 (OSI) discloses pyrrolidine- and piperidine-substitutedpurines and purine analogues having adenosine receptor binding activity.

WO 2004/043380 (Harvard College et al.) discloses technetium and rheniumlabelled imaging agents containing disubstituted piperidine metalion-chelating ligands.

WO 97/38665 (Merck) discloses gem-disubstituted piperidine derivativeshaving farnesyl transferase inhibitory activity.

EP 1568699 (Eisai) discloses 1,3-dihydroimidazole fused ring compoundshaving DPPIV-inhibiting activity. The compounds are described as havinga range of potential uses including the treatment of cancer.

US 2003/0073708 and US 2003/045536 (both in the name of Castelhano etal), WO 02/057267 (OSI Pharmaceuticals) and WO 99/62518 (CadusPharmaceutical Corporation) each disclose a class of 4-aminodeazapurinesin which the 4-amino group can form part of a cyclic amine such asazetidine, pyrrolidine and piperidine, The compounds are described ashaving adenosine receptor antagonist activity.

U.S. Pat. No. 6,162,804 (Merck) discloses a class of benzimidazole andaza-benzimidazole compounds that have tyrosine kinase inhibitoractivity.

SUMMARY OF THE INVENTION

The invention provides compounds that have protein kinase B (PKB) and/orprotein kinase A (PKA) inhibiting or modulating activity, and which itis envisaged will be useful in preventing or treating disease states orconditions mediated by PKB and/or PKA.

Accordingly, in one aspect, the invention provides a compound for use asa protein kinase B inhibitor, the compound being a compound of theformula (I):

or salts, solvates, tautomers or N-oxides thereof, wherein

-   -   T is N or a group CR⁵;    -   J¹-J² represents a group selected from N═C(R⁶), (R⁷)C═N,        (R⁸)N—C(O), (R⁸)₂C—C(O), N═N and (R⁷)C═C(R⁶);    -   E is a monocyclic carbocyclic or heterocyclic group of 5 or 6        ring members wherein the heterocyclic group contains up to 3        heteroatoms selected from O, N and S;    -   Q¹ is a bond or a saturated hydrocarbon linker group containing        from 1 to 3 carbon atoms, wherein one of the carbon atoms in the        linker group may optionally be replaced by an oxygen or nitrogen        atom, or an adjacent pair of carbon atoms may be replaced by        CONR^(q) or NR^(q)CO where R^(q) is hydrogen, C₁₋₄ alkyl or        cyclopropyl, or R^(q) is a C₁₋₄ alkylene chain that links to R¹        or to another carbon atom of Q¹ to form a cyclic moiety; and        wherein the carbon atoms of the linker group Q¹ may optionally        bear one or more substituents selected from fluorine and        hydroxy;    -   Q² is a bond or a saturated hydrocarbon linker group containing        from 1 to 3 carbon atoms, wherein one of the carbon atoms in the        linker group may optionally be replaced by an oxygen or nitrogen        atom; and wherein the carbon atoms of the linker group may        optionally bear one or more substituents selected from fluorine        and hydroxy, provided that the hydroxy group when present is not        located at a carbon atom α with respect to the G group;    -   G is selected from hydrogen, NR²R³, OH and SH with the proviso        that when E is aryl or heteroaryl and Q² is a bond, then G is        hydrogen;    -   R¹ is hydrogen or an aryl or heteroaryl group, with the proviso        that when R¹ is hydrogen and G is NR²R³, then Q² is a bond;    -   R² and R³ are independently selected from hydrogen; C₁₋₄        hydrocarbyl and C₁₋₄ acyl wherein the hydrocarbyl and acyl        groups are optionally substituted by one or more substituents        selected from fluorine, hydroxy, cyano, amino, methylamino,        dimethylamino, methoxy and a monocyclic or bicyclic aryl or        heteroaryl group;    -   or R² and R³ together with the nitrogen atom to which they are        attached form a cyclic group selected from an imidazole group        and a saturated monocyclic heterocyclic group having 4-7 ring        members and optionally containing a second heteroatom ring        member selected from O and N;    -   or one of R² and R³ together with the nitrogen atom to which        they are attached and one or more atoms from the group Q² form a        saturated monocyclic heterocyclic group having 4-7 ring members        and optionally containing a second heteroatom ring member        selected from O and N;    -   or NR²R³ when present and a carbon atom of linker group Q² to        which it is attached together form a cyano group; and    -   R⁴, R⁶ and R⁸ are each independently selected from hydrogen,        halogen, C₁₋₅ saturated hydrocarbyl, cyano, CONH₂, CONHR⁹, CF₃,        NH₂, NHCOR⁹ and NHCONHR⁹;    -   R⁵ and R⁷ are each independently selected from hydrogen,        halogen, C₁₋₅ saturated hydrocarbyl, cyano and CF₃;    -   R⁹ is phenyl or benzyl each optionally substituted by one or        substituents selected from halogen, hydroxy, trifluoromethyl,        cyano, nitro, carboxy, amino, mono- or di-C₁₋₄ hydrocarbylamino;        a group R^(a)-R^(b) wherein R^(a) is a bond, O, CO, X¹C(X²),        C(X²)X¹, X¹C(X²)X¹, S, SO, SO₂, NR^(c), SO₂NR^(c) or NR^(c)SO₂;        and R^(b) is selected from hydrogen, heterocyclic groups having        from 3 to 12 ring members, and a C₁₋₈ hydrocarbyl group        optionally substituted by one or more substituents selected from        hydroxy, oxo, halogen, cyano, nitro, carboxy, amino, mono- or        di-C₁₋₄ hydrocarbylamino, carbocyclic and heterocyclic groups        having from 3 to 12 ring members and wherein one or more carbon        atoms of the C₁₋₈ hydrocarbyl group may optionally be replaced        by O, S, SO, SO₂, NR^(c), X¹C(X²), C(X²)X¹ or X¹C(X²)X¹;    -   R^(c)C is selected from hydrogen and C₁₋₄ hydrocarbyl; and    -   X¹ is O, S or NR^(c) and X² is ═O, ═S or ═NR^(c).

In a further aspect, the invention provides a compound for use as aprotein kinase B inhibitor, the compound being a compound of the formula(Ia):

or salts, solvates, tautomers or N-oxides thereof, wherein

-   -   T is N or a group CR⁵;    -   J¹-J² represents a group selected from N═C(R⁶), (R⁷)C═N,        (R⁸)N—C(O), (R⁸)₂C—C(O), N═N and (R⁷)C═C(R⁶);    -   E is a monocyclic carbocyclic or heterocyclic group of 5 or 6        ring members wherein the heterocyclic group contains up to 3        heteroatoms selected from O, N and S;    -   Q¹ and Q² are the same or different and are each a bond or a        saturated hydrocarbon linker group containing from 1 to 3 carbon        atoms, wherein one of the carbon atoms in the linker group may        optionally be replaced by an oxygen or nitrogen atom; and        wherein the carbon atoms of the or each linker group Q¹ and Q²        may optionally bear one or more substituents selected from        fluorine and hydroxy, provided that the hydroxy group when        present is not located at a carbon atom α with respect to the G        group;    -   G is selected from hydrogen, NR²R³, OH and SH with the proviso        that when E is aryl or heteroaryl and Q² is a bond, then G is        hydrogen;    -   R¹ is hydrogen or an aryl or heteroaryl group, with the proviso        that when R¹ is hydrogen and G is NR²R³, then Q² is a bond;    -   R² and R³ are independently selected from hydrogen; C₁₋₄        hydrocarbyl and C₁₋₄ acyl wherein the hydrocarbyl and acyl        groups are optionally substituted by one or more substituents        selected from fluorine, hydroxy, amino, methylamino,        dimethylamino, methoxy and a monocyclic or bicyclic aryl or        heteroaryl group;    -   or R² and R³ together with the nitrogen atom to which they are        attached form a cyclic group selected from an imidazole group        and a saturated monocyclic heterocyclic group having 4-7 ring        members and optionally containing a second heteroatom ring        member selected from O and N;    -   or one of R² and R³ together with the nitrogen atom to which        they are attached and one or more atoms from the group Q² form a        saturated monocyclic heterocyclic group having 4-7 ring members        and optionally containing a second heteroatom ring member        selected from O and N;    -   or NR²R³ when present and a carbon atom of linker group Q² to        which it is attached together form a cyano group; and    -   R⁴, R⁶ and R⁸ are each independently selected from hydrogen,        halogen, C₁₋₅ saturated hydrocarbyl, cyano, CONH₂, CONHR⁹, CF₃,        NH₂, NHCOR⁹ and NHCONHR⁹;    -   R⁵ and R⁷ are each independently selected from hydrogen,        halogen, C₁₋₅ saturated hydrocarbyl, cyano and CF₃;    -   R⁹ is phenyl or benzyl each optionally substituted by one or        substituents selected from halogen, hydroxy, trifluoromethyl,        cyano, nitro, carboxy, amino, mono- or di-C₁₋₄ hydrocarbylamino;        a group R^(a)-R^(b) wherein R^(a) is a bond, O, CO, X¹C(X²),        C(X²)X¹, X¹C(X²)X¹, S, SO, SO₂, NR^(c), SO₂NR^(c) or NR^(c)SO₂;        and R^(b) is selected from hydrogen, heterocyclic groups having        from 3 to 12 ring members, and a C₁₋₈ hydrocarbyl group        optionally substituted by one or more substituents selected from        hydroxy, oxo, halogen, cyano, nitro, carboxy, amino, mono- or        di-C₁₋₄ hydrocarbylamino, carbocyclic and heterocyclic groups        having from 3 to 12 ring members and wherein one or more carbon        atoms of the C₁₋₈ hydrocarbyl group may optionally be replaced        by O, S, SO, SO₂, NR^(c), X¹C(X²), C(X²)X¹ or X¹C(X²)X¹;    -   R^(c) is selected from hydrogen and C₁₋₄ hydrocarbyl; and    -   X¹ is O, S or NR^(c) and X² is ═O, ═S or ═NR^(c).

In another aspect, the invention provides a compound for use as aprotein kinase B inhibitor, the compound being a compound of the formula(Ib):

or salts, solvates, tautomers or N-oxides thereof, wherein

-   -   T is N or a group CR⁵;    -   J¹-J² represents a group selected from N═C(R⁶), (R⁷)C═N,        (R⁸)N—C(O), (R⁸)₂C—C(O), N═N and (R⁷)C═C(R⁶);    -   E is a monocyclic carbocyclic or heterocyclic group of 5 or 6        ring members wherein the heterocyclic group contains up to 3        heteroatoms selected from O, N and S;    -   Q¹ and Q² are the same or different and are each a bond or a        saturated hydrocarbon linker group containing from 1 to 3 carbon        atoms, wherein one of the carbon atoms in the linker group may        optionally be replaced by an oxygen or nitrogen atom; and        wherein the carbon atoms of the or each linker group Q¹ and Q²        may optionally bear one or more substituents selected from        fluorine and hydroxy, provided that the hydroxy group when        present is not located at a carbon atom α with respect to the G        group;    -   G is selected from hydrogen, NR²R³, OH and SH with the proviso        that when E is aryl or heteroaryl and Q² is a bond, then G is        hydrogen;    -   R¹ is hydrogen or an aryl or heteroaryl group, with the proviso        that when R¹ is hydrogen and G is NR²R³, then Q² is a bond;    -   R² and R³ are independently selected from hydrogen; C₁₋₄        hydrocarbyl and C₁₋₄ acyl wherein the hydrocarbyl and acyl        groups are optionally substituted by a monocyclic or bicyclic        aryl or heteroaryl group;    -   or R² and R³ together with the nitrogen atom to which they are        attached form a saturated monocyclic heterocyclic group having        4-7 ring members and optionally containing a second heteroatom        ring member selected from O and N;    -   or one of R² and R³ together with the nitrogen atom to which        they are attached and one or more atoms from the group Q² form a        saturated monocyclic heterocyclic group having 4-7 ring members        and optionally containing a second heteroatom ring member        selected from O and N;    -   or NR²R³ when present and a carbon atom of linker group Q² to        which it is attached together form a cyano group; and    -   R⁴, R⁶ and R⁸ are each independently selected from hydrogen,        halogen, C₁₋₅ saturated hydrocarbyl, cyano, CONH₂, CONHR⁹, CF₃,        NH₂, NHCOR⁹ or NHCONHR⁹;    -   R⁵ and R⁷ are each independently selected from hydrogen,        halogen, C₁₋₅ saturated hydrocarbyl, cyano and CF₃;    -   R⁹ is phenyl or benzyl each optionally substituted by one or        substituents selected from halogen, hydroxy, trifluoromethyl,        cyano, nitro, carboxy, amino, mono- or di-C₁₋₄ hydrocarbylamino;        a group R^(a)-R^(b) wherein R^(a) is a bond; O, CO, X¹C(X²),        C(X²)X¹, X¹C(X²)X¹, S, SO, SO₂, NR^(c), SO₂NR^(c) or NR^(c)SO₂;        and R^(b) is selected from hydrogen, heterocyclic groups having        from 3 to 12 ring members, and a C₁₋₈ hydrocarbyl group        optionally substituted by one or more substituents selected from        hydroxy, oxo, halogen, cyano, nitro, carboxy, amino, mono- or        di-C₁₋₄ hydrocarbylamino, carbocyclic and heterocyclic groups        having from 3 to 12 ring members and wherein one or more carbon        atoms of the C₁₋₈ hydrocarbyl group may optionally be replaced        by O, S, SO, SO₂, NR^(c), X¹C(X²), C(X²)X¹ or X¹C(X²)X¹;    -   R^(c) is selected from hydrogen and C₁₋₄ hydrocarbyl; and    -   X¹ is O, S or NR^(c) and X² is ═O, ═S or ═NR^(c).

In another aspect, the invention provides a novel compound of theformula (Ic):

or salts, solvates, tautomers or N-oxides thereof, wherein

-   -   T is N or a group CR⁵;    -   J¹-J² represents a group selected from N═C(R⁶), (R⁷)C═N,        (R⁸)N—C(O), (R⁸)₂C—C(O), N═N and (R⁷)C═C(R⁶);    -   E is a monocyclic carbocyclic or heterocyclic group of 5 or 6        ring members wherein the heterocyclic group contains up to 3        heteroatoms selected from O, N and S;    -   Q¹ is a bond or a saturated hydrocarbon linker group containing        from 1 to 3 carbon atoms, wherein one of the carbon atoms in the        linker group may optionally be replaced by an oxygen or nitrogen        atom, or an adjacent pair of carbon atoms may be replaced by        CONR^(q) or NR^(q)CO where R^(q) is hydrogen, C₁₋₄ alkyl or        cyclopropyl, or R^(q) is a C₁₋₄ alkylene chain that links to R¹        or to another carbon atom of Q¹ to form a cyclic moiety; and        wherein the carbon atoms of the linker group Q¹ may optionally        bear one or more substituents selected from fluorine and        hydroxy;    -   Q² is a bond or a saturated hydrocarbon linker group containing        from 1 to 3 carbon atoms, wherein one of the carbon atoms in the        linker group may optionally be replaced by an oxygen or nitrogen        atom; and wherein the carbon atoms of the linker group may        optionally bear one or more substituents selected from fluorine        and hydroxy, provided that the hydroxy group when present is not        located at a carbon atom α with respect to the G group; and        provided that when E is aryl or heteroaryl, then Q² is other        than a bond;    -   R¹ is an aryl or heteroaryl group;    -   R² and R³ are independently selected from hydrogen; C₁₋₄        hydrocarbyl and C₁₋₄ acyl wherein the hydrocarbyl and acyl        groups are optionally substituted by one or more substituents        selected from fluorine, cyano, hydroxy, amino, methylamino,        dimethylamino, methoxy and a monocyclic or bicyclic aryl or        heteroaryl group;    -   or R² and R³ together with the nitrogen atom to which they are        attached form a saturated monocyclic heterocyclic group having        4-7 ring members and optionally containing a second heteroatom        ring member selected from O and N;    -   or one of R² and R³ together with the nitrogen atom to which        they are attached and one or more atoms from the group Q² form a        saturated monocyclic heterocyclic group having 4-7 ring members        and optionally containing a second heteroatom ring member        selected from O and N;    -   or NR²R³ and a carbon atom of linker group Q² to which it is        attached together form a cyano group; and    -   R⁴, R⁶ and R⁸ are each independently selected from hydrogen,        halogen, C₁₋₅ saturated hydrocarbyl, cyano, CONH₂, CONHR⁹, CF₃,        NH₂, NHCOR⁹ or NHCONHR⁹;    -   R⁵ and R⁷ are each independently selected from hydrogen,        halogen, C₁₋₅ saturated hydrocarbyl, cyano and CF₃;    -   R⁹ is phenyl or benzyl each optionally substituted by one or        substituents selected from halogen, hydroxy, trifluoromethyl,        cyano, nitro, carboxy, amino, mono- or di-C₁₋₄ hydrocarbylamino;        a group R^(a)-R^(b) wherein R^(a) is a bond, O, CO, X¹C(X²),        C(X²)X¹, X¹C(X²)X¹, S, SO, SO₂, NR^(c), SO₂NR^(c) or NR^(c)SO₂;        and R^(b) is selected from hydrogen, heterocyclic groups having        from 3 to 12 ring members, and a C₁₋₈ hydrocarbyl group        optionally substituted by one or more substituents selected from        hydroxy, oxo, halogen, cyano, nitro, carboxy, amino, mono- or        di-C₁₋₄ hydrocarbylamino, carbocyclic and heterocyclic groups        having from 3 to 12 ring members and wherein one or more carbon        atoms of the C₁₋₈ hydrocarbyl group may optionally be replaced        by O, S, SO, SO₂, NR^(c), X¹C(X²), C(X²)X¹ or X¹C(X²)X¹;    -   R^(c) is selected from hydrogen and C₁₋₄ hydrocarbyl; and    -   X¹ is O, S or NR^(c) and X² is ═O, ═S or ═NR^(c).

In another aspect, the invention provides a novel compound of theformula (Id):

or salts, solvates, tautomers or N-oxides thereof, wherein

-   -   T is N or a group CR⁵;    -   J¹-J² represents a group selected from N═C(R⁶), (R⁷)C═N,        (R⁸)N—C(O), (R⁸)₂C—C(O), N═N and (R⁷)C═C(R⁶);    -   E is a monocyclic carbocyclic or heterocyclic group of 5 or 6        ring members wherein the heterocyclic group contains up to 3        heteroatoms selected from O, N and S;    -   Q¹ and Q² are the same or different and are each a bond or a        saturated hydrocarbon linker group containing from 1 to 3 carbon        atoms, wherein one of the carbon atoms in the linker group may        optionally be replaced by an oxygen or nitrogen atom; and        wherein the carbon atoms of the or each linker group Q¹ and Q²        may optionally bear one or more substituents selected from        fluorine and hydroxy, provided that the hydroxy group when        present is not located at a carbon atom α with respect to the G        group; and provided that when E is aryl or heteroaryl, then Q²        is other than a bond;    -   R¹ is an aryl or heteroaryl group;    -   R² and R³ are independently selected from hydrogen; C₁₋₄        hydrocarbyl and C₁₋₄ acyl wherein the hydrocarbyl and acyl        groups are optionally substituted by one or more substituents        selected from fluorine, hydroxy, amino, methylamino,        dimethylamino, methoxy and a monocyclic or bicyclic aryl or        heteroaryl group;    -   or R² and R³ together with the nitrogen atom to which they are        attached form a saturated monocyclic heterocyclic group having        4-7 ring members and optionally containing a second heteroatom        ring member selected from O and N;    -   or one of R² and R³ together with the nitrogen atom to which        they are attached and one or more atoms from the group Q² form a        saturated monocyclic heterocyclic group having 4-7 ring members        and optionally containing a second heteroatom ring member        selected from O and N;    -   or NR²R³ and a carbon atom of linker group Q² to which it is        attached together form a cyano group; and    -   R⁴, R⁶ and R⁸ are each independently selected from hydrogen,        halogen, C₁₋₅ saturated hydrocarbyl, cyano, CONH₂, CONHR⁹, CF₃,        NH₂, NHCOR⁹ or NHCONHR⁹;    -   R⁵ and R⁷ are each independently selected from hydrogen,        halogen, C₁₋₅ saturated hydrocarbyl, cyano and CF₃;    -   R⁹ is phenyl or benzyl each optionally substituted by one or        substituents selected from halogen, hydroxy, trifluoromethyl,        cyano, nitro, carboxy, amino, mono- or di-C₁₋₄ hydrocarbylamino;        a group R^(a)-R^(b) wherein R^(a) is a bond, O, CO, X¹C(X²),        C(X²)X¹, X¹C(X²)X¹, S, SO, SO₂, NR^(c), SO₂NR^(c) or NR^(c)SO₂;        and R^(b) is selected from hydrogen, heterocyclic groups having        from 3 to 12 ring members, and a C₁₋₈ hydrocarbyl group        optionally substituted by one or more substituents selected from        hydroxy, oxo, halogen, cyano, nitro, carboxy, amino, mono- or        di-C₁₋₄ hydrocarbylamino, carbocyclic and heterocyclic groups        having from 3 to 12 ring members and wherein one or more carbon        atoms of the C₁₋₈ hydrocarbyl group may optionally be replaced        by O, S, SO, SO₂, NR^(c), X¹C(X²), C(X²)X¹ or X¹C(X²)X¹;    -   R^(c) is selected from hydrogen and C₁₋₄ hydrocarbyl; and    -   X¹ is O, S or NR^(c) and X² is ═O, ═S or ═NR^(c).

The invention also provides:

-   -   A compound per se of the formula (II), (III), (IV), (V), (VII)        or any other sub-group or embodiment of the formula (I) as        defined herein.    -   A compound of the formula (I), (Ia), (Ib), (Ic), (Id), (II),        (IIa), (III), (IV), (V), (VI), (VII) or any sub-group thereof as        defined herein for use in the prophylaxis or treatment of a        disease state or condition mediated by protein kinase B.    -   The use of a compound of formula (I), (Ia), (Ib), (Ic), (Id),        (II), (IIa), (III), (IV), (V), (VI), (VII) or any sub-group        thereof as defined herein for the manufacture of a medicament        for the prophylaxis or treatment of a disease state or condition        mediated by protein kinase B.    -   A method for the prophylaxis or treatment of a disease state or        condition mediated by protein kinase B, which method comprises        administering to a subject in need thereof a compound of the        formula (I), (Ia), (Ib), (Ic), (Id), (II), (IIa), (III), (IV),        (V), (VI), (VII) or any sub-group thereof as defined herein.    -   A method for treating a disease or condition comprising or        arising from abnormal cell growth or abnormally arrested cell        death in a mammal, the method comprising administering to the        mammal a compound of the formula (I), (Ia), (Ib), (Ic), (Id),        (II), (IIa), (III), (IV), (V), (VI), (VII) or any sub-group        thereof as defined herein in an amount effective to inhibit        protein kinase B activity.    -   A method of inhibiting protein kinase B, which method comprises        contacting the kinase with a kinase-inhibiting compound of the        formula (I), (Ia), (Ib), (Ic), (Id), (II), (IIa), (III), (IV),        (V), (VI), (VII) or any sub-group thereof as defined herein.    -   A method of modulating a cellular process (for example cell        division) by inhibiting the activity of a protein kinase B using        a compound of the formula (I), (Ia), (Ib), (Ic), (Id), (II),        (IIa), (III), (IV), (V), (VI), (VII) or any sub-group thereof as        defined herein.    -   A compound of the formula (I), (Ia), (Ib), (Ic), (Id), (II),        (Ia), (III), (IV), (V), (VI), (VII) or any sub-group or        embodiment thereof as defined herein for use in the prophylaxis        or treatment of a disease state or condition mediated by protein        kinase A.    -   The use of a compound of formula (I), (Ia), (Ib), (Ic), (Id),        (II), (Ia), (III), (IV), (V), (VI), (VII) or any sub-group or        embodiment thereof as defined herein for the manufacture of a        medicament for the prophylaxis or treatment of a disease state        or condition mediated by protein kinase A.    -   A method for the prophylaxis or treatment of a disease state or        condition mediated by protein kinase A, which method comprises        administering to a subject in need thereof a compound of the        formula (I), (Ia), (Ib), (Ic), (Id), (II), (IIa), (III), (IV),        (V), (VI), (VII) or any sub-group or embodiment thereof as        defined herein.    -   A method for treating a disease or condition comprising or        arising from abnormal cell growth or abnormally arrested cell        death in a mammal, the method comprising administering to the        mammal a compound of the formula (I), (Ia), (Ib), (Ic), (Id),        (II), (IIa), (III), (IV), (V), (VI), (VII) or any sub-group or        embodiment thereof as defined herein in an amount effective to        inhibit protein kinase A activity.    -   A method of inhibiting protein kinase A, which method comprises        contacting the kinase with a kinase-inhibiting compound of the        formula (I), (Ia), (Ib), (Ic), (Id), (II), (IIa), (III), (IV),        (V), (VI), (VII) or any sub-group or embodiment thereof as        defined herein.    -   A method of modulating a cellular process (for example cell        division) by inhibiting the activity of a protein kinase A using        a compound of the formula (I), (Ia), (Ib), (Ic), (Id), (II),        (IIa), (III), (IV), (V), (VI), (VII) or any sub-group or        embodiment thereof as defined herein.

The use of a compound of the formula (I), (Ia), (Ib), (Ic), (Id), (II),(IIa), (III), (IV), (V), (VI), (VII) or any sub-group thereof as definedherein for the manufacture of a medicament for the prophylaxis ortreatment of a disease state or condition arising from abnormal cellgrowth or abnormally arrested cell death.

-   -   A method for treating a disease or condition comprising or        arising from abnormal cell growth in a mammal, which method        comprises administering to the mammal a compound of the formula        (I), (Ia), (Ib), (Ic), (Id), (II), (IIa), (III), (IV), (V),        (VI), (VII) or any sub-group thereof as defined herein in an        amount effective in inhibiting abnormal cell growth or        abnormally arrested cell death.    -   A method for alleviating or reducing the incidence of a disease        or condition comprising or arising from abnormal cell growth or        abnormally arrested cell death in a mammal, which method        comprises administering to the mammal a compound of the formula        (I), (Ia), (Ib), (Ic), (Id), (II), (IIa), (III), (IV), (V),        (VI), (VII) or any sub-group thereof as defined herein in an        amount effective in inhibiting abnormal cell growth.    -   A pharmaceutical composition comprising a novel compound of the        formula (I), (Ia), (Ib), (Ic), (Id), (II), (IIa), (III), (IV),        (V), (VI), (VII) or any sub-group thereof as defined herein and        a pharmaceutically acceptable carrier.    -   A compound of the formula (I), (Ia), (Ib), (Ic), (Id), (II),        (IIa), (III), (IV), (V), (VI), (VII) or any sub-group thereof as        defined herein for use in medicine.    -   The use of a compound of the formula (I), (Ia), (Ib), (Ic),        (Id), (II), (IIa), (III), (IV), (V), (VI), (VII) or any        sub-group thereof as defined herein for the manufacture of a        medicament for the prophylaxis or treatment of any one of the        disease states or conditions disclosed herein.    -   A method for the treatment or prophylaxis of any one of the        disease states or conditions disclosed herein, which method        comprises administering to a patient (e.g. a patient in need        thereof) a compound (e.g. a therapeutically effective amount) of        the formula (I), (Ia), (Ib), (Ic), (Id), (II), (IIa), (III),        (IV), (V), (VI), (VII) or any sub-group thereof as defined        herein.    -   A method for alleviating or reducing the incidence of a disease        state or condition disclosed herein, which method comprises        administering to a patient (e.g. a patient in need thereof) a        compound (e.g. a therapeutically effective amount) of the        formula (I), (Ia), (Ib), (Ic), (Id), (II), (Ia), (III), (IV),        (V), (VI), (VII) or any sub-group thereof as defined herein.    -   A method for the diagnosis and treatment of a disease state or        condition mediated by protein kinase B, which method        comprises (i) screening a patient to determine whether a disease        or condition from which the patient is or may be suffering is        one which would be susceptible to treatment with a compound        having activity against protein kinase B; and (ii) where it is        indicated that the disease or condition from which the patient        is thus susceptible, thereafter administering to the patient a        compound of the formula (I), (Ia), (Ib), (Ic), (Id), (II),        (IIa), (III), (IV), (V), (VI), (VII) or any sub-group thereof as        defined herein.    -   The use of a compound of the formula (I), (Ia), (Ib), (Ic),        (Id), (II), (IIa), (III), (IV), (V), (VI), (VII) or any        sub-group thereof as defined herein for the manufacture of a        medicament for the treatment or prophylaxis of a disease state        or condition in a patient who has been screened and has been        determined as suffering from, or being at risk of suffering        from, a disease or condition which would be susceptible to        treatment with a compound having activity against protein kinase        B.    -   A method for the diagnosis and treatment of a disease state or        condition mediated by protein kinase A, which method        comprises (i) screening a patient to determine whether a disease        or condition from which the patient is or may be suffering is        one which would be susceptible to treatment with a compound        having activity against protein kinase A; and (ii) where it is        indicated that the disease or condition from which the patient        is thus susceptible, thereafter administering to the patient a        compound of the formula (I), (Ia), (Ib), (Ic), (Id), (II),        (IIa), (III), (IV), (V), (VI), (VII) or any sub-group or        embodiment thereof as defined herein.    -   The use of a compound of the formula (I), (Ia), (Ib), (Ic),        (Id), (II), (IIa), (III), (IV), (V), (VI), (VII) or any        sub-group or embodiment thereof as defined herein for the        manufacture of a medicament for the treatment or prophylaxis of        a disease state or condition in a patient who has been screened        and has been determined as suffering from, or being at risk of        suffering from, a disease or condition which would be        susceptible to treatment with a compound having activity against        protein kinase A.

Any one or more of the following optional provisos may apply in anycombination to any one of the formulae (I), (Ia), (Ib), (Ic), (Id),(II), (IIa), (III), (IV), (V), (VI), (VII) and any sub-groups andembodiments as defined herein.

(i) When J¹-J² is (R⁷)C═C(R⁶) and R¹ is an aryl or heteroaryl group, thearyl or heteroaryl group bears one or more substituents (i.e. a moietyother than hydrogen) as defined herein.(ii) When Q¹ is a bond, and E is a piperazine group, R¹ is other than asubstituted pyridyl group linked to a nitrogen atom of the piperazinegroup wherein the substituted pyridyl group is substituted by an amidemoiety.(iii) When Q¹ contains a nitrogen atom and the moiety Q²-G contains aheterocyclic group, R¹ is other than a substituted aminoquinoxalinegroup.

GENERAL PREFERENCES AND DEFINITIONS

The following general preferences and definitions shall apply to each ofthe moieties T, E, G, Q¹, Q²J¹, J², T and R¹ to R⁹ and anysub-definition, sub-group or embodiment thereof, unless the contextindicates otherwise.

Any references to Formula (I) herein shall be taken also to refer toformulae (Ia), (Ib), (Ic), (Id), (Ie), (II), (IIa), (III), (IV), (V),(VI), (VII) and any other sub-group of compounds within formula (I)), orembodiment thereof, unless the context requires otherwise.

In this specification, references to “the bicyclic group”, when used inregard to the point of attachment of the group E shall, unless thecontext indicates otherwise, be taken to refer to the group:

References to “carbocyclic” and “heterocyclic” groups as used hereinshall, unless the context indicates otherwise, include both aromatic andnon-aromatic ring systems. In general, such groups may be monocyclic orbicyclic and may contain, for example, 3 to 12 ring members, moreusually 5 to 10 ring members. Examples of monocyclic groups are groupscontaining 3, 4, 5, 6, 7, and 8 ring members, more usually 3 to 7, andpreferably 5 or 6 ring members. Examples of bicyclic groups are thosecontaining 8, 9, 10, 11 and 12 ring members, and more usually 9 or 10ring members.

The carbocyclic or heterocyclic groups can be aryl or heteroaryl groupshaving from 5 to 12 ring members, more usually from 5 to 10 ringmembers. The term “aryl” as used herein refers to a carbocyclic grouphaving aromatic character and the term “heteroaryl” is used herein todenote a heterocyclic group having aromatic character. The terms “aryl”and “heteroaryl” embrace polycyclic (e.g. bicyclic) ring systems whereinone or more rings are non-aromatic, provided that at least one ring isaromatic. In such polycyclic systems, the group may be attached by thearomatic ring, or by a non-aromatic ring. The aryl or heteroaryl groupscan be monocyclic or bicyclic groups and can be unsubstituted orsubstituted with one or more substituents, for example one or moregroups R¹⁰ as defined herein.

The term non-aromatic group embraces unsaturated ring systems withoutaromatic character, partially saturated and fully saturated carbocyclicand heterocyclic ring systems. The terms “unsaturated” and “partiallysaturated” refer to rings wherein the ring structure(s) contains atomssharing more than one valence bond i.e. the ring contains at least onemultiple bond e.g. a C═C, C≡C or N═C bond. The term “fully saturated”refers to rings where there are no multiple bonds between ring atoms.Saturated carbocyclic groups include cycloalkyl groups as defined below.Partially saturated carbocyclic groups include cycloalkenyl groups asdefined below, for example cyclopentenyl, cycloheptenyl andcyclooctenyl.

Examples of heteroaryl groups are monocyclic and bicyclic groupscontaining from five to twelve ring members, and more usually from fiveto ten ring members. The heteroaryl group can be, for example, a fivemembered or six membered monocyclic ring or a bicyclic structure formedfrom fused five and six membered rings or two fused six membered rings.Each ring may contain up to about four heteroatoms typically selectedfrom nitrogen, sulphur and oxygen. Typically the heteroaryl ring willcontain up to 3 heteroatoms, more usually up to 2, for example a singleheteroatom. In one embodiment, the heteroaryl ring contains at least onering nitrogen atom. The nitrogen atoms in the heteroaryl rings can bebasic, as in the case of an imidazole or pyridine, or essentiallynon-basic as in the case of an indole or pyrrole nitrogen. In generalthe number of basic nitrogen atoms present in the heteroaryl group,including any amino group substituents of the ring, will be less thanfive.

Examples of five membered heteroaryl groups include but are not limitedto pyrrole, furan, thiophene, imidazole, furazan, oxazole, oxadiazole,oxatriazole, isoxazole, thiazole, isothiazole, pyrazole, triazole andtetrazole groups.

Examples of six membered heteroaryl groups include but are not limitedto pyridine, pyrazine, pyridazine, pyrimidine and triazine.

A bicyclic heteroaryl group may be, for example, a group selected from:

-   -   a) a benzene ring fused to a 5- or 6-membered ring containing 1,        2 or 3 ring heteroatoms;    -   b) a pyridine ring fused to a 5- or 6-membered ring containing        1, 2 or 3 ring heteroatoms;    -   c) a pyrimidine ring fused to a 5- or 6-membered ring containing        1 or 2 ring heteroatoms;    -   d) a pyrrole ring fused to a a 5- or 6-membered ring containing        1, 2 or 3 ring heteroatoms;    -   e) a pyrazole ring fused to a a 5- or 6-membered ring containing        1 or 2 ring heteroatoms;    -   f) a pyrazine ring fused to a 5- or 6-membered ring containing 1        or 2 ring heteroatoms;    -   g) an imidazole ring fused to a 5- or 6-membered ring containing        1 or 2 ring heteroatoms;    -   h) an oxazole ring fused to a 5- or 6-membered ring containing 1        or 2 ring heteroatoms;    -   i) an isoxazole ring fused to a 5- or 6-membered ring containing        1 or 2 ring heteroatoms;    -   j) a thiazole ring fused to a 5- or 6-membered ring containing 1        or 2 ring heteroatoms;    -   k) an isothiazole ring fused to a 5- or 6-membered ring        containing 1 or 2 ring heteroatoms;    -   l) a thiophene ring fused to a 5- or 6-membered ring containing        1, 2 or 3 ring heteroatoms;    -   m) a furan ring fused to a 5- or 6-membered ring containing 1, 2        or 3 ring heteroatoms;    -   n) a cyclohexyl ring fused to a 5- or 6-membered ring containing        1, 2 or 3 ring heteroatoms; and    -   o) a cyclopentyl ring fused to a 5- or 6-membered ring        containing 1, 2 or 3 ring heteroatoms.

Particular examples of bicyclic heteroaryl groups containing a sixmembered ring fused to a five membered ring include but are not limitedto benzfuran, benzthiophene, benzimidazole, benzoxazole, benzisoxazole,benzthiazole, benzisothiazole, isobenzofuran, indole, isoindole,indolizine, indoline, isoindoline, purine (e.g., adenine, guanine),indazole, benzodioxole and pyrazolopyridine groups.

Particular examples of bicyclic heteroaryl groups containing two fusedsix membered rings include but are not limited to quinoline,isoquinoline, chroman, thiochroman, chromene, isochromene, chroman,isochroman, benzodioxan, quinolizine, benzoxazine, benzodiazine,pyridopyridine, quinoxaline, quinazoline, cinnoline, phthalazine,naphthyridine and pteridine groups.

Examples of polycyclic aryl and heteroaryl groups containing an aromaticring and a non-aromatic ring include tetrahydronaphthalene,tetrahydroisoquinoline, tetrahydroquinoline, dihydrobenzthiene,dihydrobenzfuran, 2,3-dihydro-benzo[1,4]dioxine, benzo[1,3]dioxole,4,5,6,7-tetrahydrobenzofuran, indoline and indane groups.

Examples of carbocyclic aryl groups include phenyl, naphthyl, indenyl,and tetrahydronaphthyl groups.

Examples of non-aromatic heterocyclic groups include unsubstituted orsubstituted (by one or more groups R¹⁰) heterocyclic groups having from3 to 12 ring members, typically 4 to 12 ring members, and more usuallyfrom 5 to 10 ring members. Such groups can be monocyclic or bicyclic,for example, and typically have from 1 to 5 heteroatom ring members(more usually 1, 2, 3 or 4 heteroatom ring members) typically selectedfrom nitrogen, oxygen and sulphur.

When sulphur is present, it may, where the nature of the adjacent atomsand groups permits, exist as —S—, —S(O)— or —S(O)₂—.

The heterocylic groups can contain, for example, cyclic ether moieties(e.g. as in tetrahydrofuran and dioxane), cyclic thioether moieties(e.g. as in tetrahydrothiophene and dithiane), cyclic amine moieties(e.g. as in pyrrolidine), cyclic amide moieties (e.g. as inpyrrolidone), cyclic urea moieties (e.g. as in imidazolidin-2-one),cyclic thiourea moieties, cyclic thioamides, cyclic thioesters, cyclicester moieties (e.g. as in butyrolactone), cyclic sulphones (e.g. as insulpholane and sulpholene), cyclic sulphoxides, cyclic sulphonamides andcombinations thereof (e.g. morpholine and thiomorpholine and its S-oxideand S,S-dioxide).

Examples of monocyclic non-aromatic heterocyclic groups include 5-, 6-and 7-membered monocyclic heterocyclic groups. Particular examplesinclude morpholine, thiomorpholine and its S-oxide and S,S-dioxide(particularly thiomorpholine), piperidine (e.g. 1-piperidinyl,2-piperidinyl 3-piperidinyl and 4-piperidinyl), N-alkyl piperidines suchas N-methyl piperidine, piperidone, pyrrolidine (e.g. 1-pyrrolidinyl,2-pyrrolidinyl and 3-pyrrolidinyl), pyrrolidone, azetidine, pyran(2H-pyran or 4H-pyran), dihydrothiophene, dihydropyran, dihydrofuran,dihydrothiazole, tetrahydrofuran, tetrahydrothiophene, dioxane,tetrahydropyran (e.g. 4-tetrahydro pyranyl), imidazoline,imidazolidinone, oxazoline, thiazoline, 2-pyrazoline, pyrazolidine,piperazone, piperazine, and N-alkyl piperazines such as N-methylpiperazine, N-ethyl piperazine and N-isopropylpiperazine. In general,preferred non-aromatic heterocyclic groups include piperidine,pyrrolidine, azetidine, morpholine, piperazine and N-alkyl piperazines.

Examples of non-aromatic carbocyclic groups include cycloalkane groupssuch as cyclohexyl and cyclopentyl, cycloalkenyl groups such ascyclopentenyl, cyclohexenyl, cycloheptenyl and cyclooctenyl, as well ascyclohexadienyl, cyclooctatetraene, tetrahydronaphthenyl and decalinyl.

Preferred non-aromatic carbocyclic groups are monocyclic rings and mostpreferably saturated monocyclic rings.

Typical examples are three, four, five and six membered saturatedcarbocyclic rings, e.g. optionally substituted cyclopentyl andcyclohexyl rings.

One sub-set of non-aromatic carbocyclic groups includes unsubstituted orsubstituted (by one or more groups R¹⁰) monocyclic groups andparticularly saturated monocyclic groups, e.g. cycloalkyl groups.Examples of such cycloalkyl groups include cyclopropyl, cyclobutyl,cyclopentyl, cyclohexyl and cycloheptyl; more typically cyclopropyl,cyclobutyl, cyclopentyl and cyclohexyl, particularly cyclohexyl.

Further examples of non-aromatic cyclic groups include bridged ringsystems such as bicycloalkanes and azabicycloalkanes although suchbridged ring systems are generally less preferred. By “bridged ringsystems” is meant ring systems in which two rings share more than twoatoms, see for example Advanced Organic Chemistry, by Jerry March, 4thEdition, Wiley Interscience, pages 131-133, 1992. Examples of bridgedring systems include bicyclo[2.2.1]heptane, aza-bicyclo[2.2.1]heptane,bicyclo[2.2.2]octane, aza-bicyclo[2.2.2]octane, bicyclo[3.2.1]octane andaza-bicyclo[3.2.1]octane.

Where reference is made herein to carbocyclic and heterocyclic groups,the carbocyclic or heterocyclic ring can, unless the context indicatesotherwise, be unsubstituted or substituted by one or more substituentgroups R¹⁰ selected from halogen, hydroxy, trifluoromethyl, cyano,nitro, carboxy, amino, mono- or di-C₁₋₄ hydrocarbylamino, carbocyclicand heterocyclic groups having from 3 to 12 ring members; a groupR^(a)-R^(b) wherein R^(a) is a bond, O, CO, X¹C(X²), C(X²)X¹, X¹C(X²)X¹,S, SO, SO₂, NR^(c), SO₂NR^(c) or NR^(c)SO₂; and R^(b) is selected fromhydrogen, carbocyclic and heterocyclic groups having from 3 to 12 ringmembers, and a C₁₋₈ hydrocarbyl group optionally substituted by one ormore substituents selected from hydroxy, oxo, halogen, cyano, nitro,carboxy, amino, mono- or di-C₁₋₄ hydrocarbylamino, carbocyclic andheterocyclic groups having from 3 to 12 ring members and wherein one ormore carbon atoms of the C₁₋₈ hydrocarbyl group may optionally bereplaced by O, S, SO, SO₂, NR^(c), X¹C(X²), C(X²)X¹ or X¹C(X²)X¹;

-   -   R^(c) is selected from hydrogen and C₁₋₄ hydrocarbyl; and    -   X¹ is O, S or NR^(c) and X² is ═O, ═S or ═NR^(c).

Where the substituent group R¹⁰ comprises or includes a carbocyclic orheterocyclic group, the said carbocyclic or heterocyclic group may beunsubstituted or may itself be substituted with one or more furthersubstituent groups R¹⁰. In one sub-group of compounds of the formula(I), such further substituent groups R¹⁰ may include carbocyclic orheterocyclic groups, which are typically not themselves furthersubstituted. In another sub-group of compounds of the formula (I), thesaid further substituents do not include carbocyclic or heterocyclicgroups but are otherwise selected from the groups listed above in thedefinition of R¹⁰.

The substituents R¹⁰ may be selected such that they contain no more than20 non-hydrogen atoms, for example, no more than 15 non-hydrogen atoms,e.g. no more than 12, or 10, or 9, or 8, or 7, or 6, or 5 non-hydrogenatoms.

One sub-group of substituents R¹⁰ is represented by R^(10a) whichconsists of substituents selected from halogen, hydroxy,trifluoromethyl, cyano, nitro, carboxy, amino, mono- or di-C₁₋₄hydrocarbylamino, carbocyclic and heterocyclic groups having from 3 to 7ring members; a group R^(a)-R^(b) wherein R^(a) is a bond, O, CO, OC(O),NR^(c)C(O), OC(NR^(c)), C(O)O, C(O)NR^(c), OC(O)O, NR^(c)C(O)O,OC(O)NR^(c), NR^(c)C(O)NR^(c), S, SO, SO₂, NR^(c), SO₂NR^(c) orNR^(c)SO₂; and R^(b) is selected from hydrogen, carbocyclic andheterocyclic groups having from 3 to 7 ring members, and a C₁₋₈hydrocarbyl group optionally substituted by one or more substituentsselected from hydroxy, oxo, halogen, cyano, nitro, carboxy, amino, mono-or di-C₁₋₄ hydrocarbylamino, carbocyclic and heterocyclic groups havingfrom 3 to 7 ring members and wherein one or more carbon atoms of theC₁₋₈ hydrocarbyl group may optionally be replaced by O, S, SO, SO₂,NR^(c), OC(O), NR^(c)C(O), OC(NR^(c)), C(O)O, C(O)NR^(c), OC(O)O,NR^(c)C(O)O, OC(O)NR^(c) or NR^(c)C(O)NR^(c);

R^(c)C is selected from hydrogen and C₁₋₄ hydrocarbyl.

Another sub-group of substituents R¹⁰ is represented by R^(10b) whichconsists of substituents selected from halogen, hydroxy,trifluoromethyl, cyano, amino, mono- or di-C₁₋₄alkylamino,cyclopropylamino, carbocyclic and heterocyclic groups having from 3 to 7ring members; a group R^(a)-R^(b) wherein R^(a) is a bond, O, CO, OC(O),NR^(c)C(O), OC(NR^(c)), C(O)O, C(O)NR^(c), S, SO, SO₂, NR^(c), SO₂NR^(c)or NR^(c)SO₂; and R^(b) is selected from hydrogen, carbocyclic andheterocyclic groups having from 3 to 7 ring members, and a C₁₋₈hydrocarbyl group optionally substituted by one or more substituentsselected from hydroxy, oxo, halogen, cyano, amino, mono- or di-C₁₋₄alkylamino, carbocyclic and heterocyclic groups having from 3 to 7 ringmembers and wherein one or more carbon atoms of the C₁₋₈ hydrocarbylgroup may optionally be replaced by O, S, SO, SO₂ or NR^(c); providedthat R^(a) is not a bond when R^(b) is hydrogen; and

R^(c) is selected from hydrogen and C₁₋₄alkyl.

A further sub-group of substituents R¹⁰ is represented by R^(10c) whichconsists of substituents selected from:

halogen,hydroxy,trifluoromethyl,cyano,amino, mono- or di-C₁₋₄ alkylamino,cyclopropylamino,monocyclic carbocyclic and heterocyclic groups having from 3 to 7 ringmembers of which 0, 1 or 2 are selected from O, N and S and theremainder are carbon atoms, wherein the monocyclic carbocyclic andheterocyclic groups are optionally substituted by one or moresubstituents selected from halogen, hydroxy, trifluoromethyl, cyano andmethoxy;a group R^(a)-R^(b);R^(a) is a bond, O, CO, OC(O), NR^(c)C(O), OC(NR^(c)), C(O)O,C(O)NR^(c), S, SO, SO₂, NR^(c), SO₂NR^(c) or NR^(c)SO₂;R^(b) is selected from hydrogen, monocyclic carbocyclic and heterocyclicgroups having from 3 to 7 ring members of which 0, 1 or 2 are selectedfrom O, N and S and the remainder are carbon atoms, wherein themonocyclic carbocyclic and heterocyclic groups are optionallysubstituted by one or more substituents selected from halogen, hydroxy,trifluoromethyl, cyano and methoxy;and R^(b) is further selected from a C₁₋₈ hydrocarbyl group optionallysubstituted by one or more substituents selected from hydroxy, oxo,halogen, cyano, amino, mono- or di-C₁₋₄ alkylamino, monocycliccarbocyclic and heterocyclic groups having from 3 to 7 ring members ofwhich 0, 1 or 2 are selected from O, N and S and the remainder arecarbon atoms, wherein the monocyclic carbocyclic and heterocyclic groupsare optionally substituted by one or more substituents selected fromhalogen, hydroxy, trifluoromethyl, cyano and methoxy, and wherein one ortwo carbon atoms of the C₁₋₈ hydrocarbyl group may optionally bereplaced by O, S or NR^(c); provided that R^(a) is not a bond when R^(b)is hydrogen; andR^(c) is selected from hydrogen and C₁₋₄ alkyl.

Where the carbocyclic and heterocyclic groups have a pair ofsubstituents on adjacent ring atoms, the two substituents may be linkedso as to form a cyclic group. For example, an adjacent pair ofsubstituents on adjacent carbon atoms of a ring may be linked via one ormore heteroatoms and optionally substituted alkylene groups to form afused oxa-, dioxa-, aza-, diaza- or oxa-aza-cycloalkyl group. Examplesof such linked substituent groups include:

Examples of halogen substituents include fluorine, chlorine, bromine andiodine. Fluorine and chlorine are particularly preferred.

In the definition of the compounds of the formula (I) above and as usedhereinafter, the term “hydrocarbyl” is a generic term encompassingaliphatic, alicyclic and aromatic groups having an all-carbon backboneand consisting of carbon and hydrogen atoms, except where otherwisestated.

In certain cases, as defined herein, one or more of the carbon atomsmaking up the carbon backbone may be replaced by a specified atom orgroup of atoms. Examples of hydrocarbyl groups include alkyl,cycloalkyl, cycloalkenyl, carbocyclic aryl, alkenyl, alkynyl,cycloalkylalkyl, cycloalkenylalkyl, and carbocyclic aralkyl, aralkenyland aralkynyl groups. Such groups can be unsubstituted or, where stated,can be substituted by one or more substituents as defined herein. Theexamples and preferences expressed below apply to each of thehydrocarbyl substituent groups or hydrocarbyl-containing substituentgroups referred to in the various definitions of substituents forcompounds of the formula (I) and sub-groups thereof as defined hereinunless the context indicates otherwise.

Generally by way of example, the hydrocarbyl groups can have up to eightcarbon atoms, unless the context requires otherwise. Within the sub-setof hydrocarbyl groups having 1 to 8 carbon atoms, particular examplesare C₁₋₆ hydrocarbyl groups, such as C₁₋₄ hydrocarbyl groups (e.g. C₁₋₃hydrocarbyl groups or C₁₋₂ hydrocarbyl groups), specific examples beingany individual value or combination of values selected from C₁, C₂, C₃,C₄, C₅, C₆, C₇ and C₈ hydrocarbyl groups.

The term “saturated hydrocarbyl”, whether used alone or together with asuffix such as “oxy” (e.g. as in “hydrocarbyloxy”), refers to anon-aromatic hydrocarbon group containing no multiple bonds such as C═Cand C≡C.

Particular hydrocarbyl groups are saturated hydrocarbyl groups such asalkyl and cycloalkyl groups as defined herein.

The term “alkyl” covers both straight chain and branched chain alkylgroups. Examples of alkyl groups include methyl, ethyl, propyl,isopropyl, n-butyl, isobutyl, tert-butyl, n-pentyl, 2-pentyl, 3-pentyl,2-methyl butyl, 3-methyl butyl, and n-hexyl and its isomers. Within thesub-set of alkyl groups having 1 to 8 carbon atoms, particular examplesare C₁₋₆ alkyl groups, such as C₁₋₄ alkyl groups (e.g. C₁₋₃ alkyl groupsor C₁₋₂ alkyl groups).

Examples of cycloalkyl groups are those derived from cyclopropane,cyclobutane, cyclopentane, cyclohexane and cycloheptane. Within thesub-set of cycloalkyl groups the cycloalkyl group will have from 3 to 8carbon atoms, particular examples being C₃₋₆ cycloalkyl groups.

Examples of alkenyl groups include, but are not limited to, ethenyl(vinyl), 1-propenyl, 2-propenyl (allyl), isopropenyl, butenyl,buta-1,4-dienyl, pentenyl, and hexenyl. Within the sub-set of alkenylgroups the alkenyl group will have 2 to 8 carbon atoms, particularexamples being C₁₋₆ alkenyl groups, such as C₂₋₄ alkenyl groups.

Examples of cycloalkenyl groups include, but are not limited to,cyclopropenyl, cyclobutenyl, cyclopentenyl, cyclopentadienyl andcyclohexenyl. Within the sub-set of cycloalkenyl groups the cycloalkenylgroups have from 3 to 8 carbon atoms, and particular examples are C₃₋₆cycloalkenyl groups.

Examples of alkynyl groups include, but are not limited to, ethynyl and2-propynyl (propargyl) groups. Within the sub-set of alkynyl groupshaving 2 to 8 carbon atoms, particular examples are C₂₋₆ alkynyl groups,such as C₂₋₄ alkynyl groups.

Examples of carbocyclic aryl groups include substituted andunsubstituted phenyl, naphthyl, indane and indene groups.

Examples of cycloalkylalkyl, cycloalkenylalkyl, carbocyclic aralkyl,aralkenyl and aralkynyl groups include phenethyl, benzyl, styryl,phenylethynyl, cyclohexylmethyl, cyclopentylmethyl, cyclobutylmethyl,cyclopropylmethyl and cyclopentenylmethyl groups.

When present, and where stated, a hydrocarbyl group can be optionallysubstituted by one or more substituents selected from hydroxy, oxo,alkoxy, carboxy, halogen, cyano, nitro, amino, mono- or di-C₁₋₄hydrocarbylamino, and monocyclic or bicyclic carbocyclic andheterocyclic groups having from 3 to 12 (typically 3 to 10 and moreusually 5 to 10) ring members. Preferred substituents include halogensuch as fluorine. Thus, for example, the substituted hydrocarbyl groupcan be a partially fluorinated or perfluorinated group such asdifluoromethyl or trifluoromethyl. In one embodiment preferredsubstituents include monocyclic carbocyclic and heterocyclic groupshaving 3-7 ring members.

Where stated, one or more carbon atoms of a hydrocarbyl group mayoptionally be replaced by O, S, SO, SO₂, NR^(c), X¹C(X²), C(X²)X¹ orX¹C(X²)X¹ (or a sub-group thereof) wherein X¹ and X² are as hereinbeforedefined, provided that at least one carbon atom of the hydrocarbyl groupremains. For example, 1, 2, 3 or 4 carbon atoms of the hydrocarbyl groupmay be replaced by one of the atoms or groups listed, and the replacingatoms or groups may be the same or different. In general, the number oflinear or backbone carbon atoms replaced will correspond to the numberof linear or backbone atoms in the group replacing them. Examples ofgroups in which one or more carbon atom of the hydrocarbyl group havebeen replaced by a replacement atom or group as defined above includeethers and thioethers (C replaced by O or S), amides, esters, thioamidesand thioesters (C—C replaced by X¹C(X²) or C(X²)X¹), sulphones andsulphoxides (C replaced by SO or SO₂), amines (C replaced by NR^(c)).Further examples include ureas, carbonates and carbamates (C—C—Creplaced by X¹C(X²)X¹).

Where an amino group has two hydrocarbyl substituents, they may,together with the nitrogen atom to which they are attached, andoptionally with another heteroatom such as nitrogen, sulphur, or oxygen,link to form a ring structure of 4 to 7 ring members.

The term “aza-cycloalkyl” as used herein refers to a cycloalkyl group inwhich one of the carbon ring members has been replaced by a nitrogenatom. Thus examples of aza-cycloalkyl groups include piperidine andpyrrolidine. The term “oxa-cycloalkyl”as used herein refers to acycloalkyl group in which one of the carbon ring members has beenreplaced by an oxygen atom. Thus examples of oxa-cycloalkyl groupsinclude tetrahydrofuran and tetrahydropyran. In an analogous manner, theterms “diaza-cycloalkyl”, “dioxa-cycloalkyl” and “aza-oxa-cycloalkyl”refer respectively to cycloalkyl groups in which two carbon ring membershave been replaced by two nitrogen atoms, or by two oxygen atoms, or byone nitrogen atom and one oxygen atom.

The definition “R^(a)-R^(b)” as used herein, either with regard tosubstituents present on a carbocyclic or heterocyclic moiety, or withregard to other substituents present at other locations on the compoundsof the formula (I), includes inter alia compounds wherein R^(a) isselected from a bond, O, CO, OC(O), SC(O), NR^(c)C(O), OC(S), SC(S),NR^(c)C(S), OC(NR^(c)), SC(NR^(c)), NR^(c)C(NR^(c)), C(O)O, C(O)S,C(O)NR^(c), C(S)O, C(S)S, C(S)NR^(c), C(NR^(c))O, C(NR^(c))S,C(NR^(c))NR^(c), OC(O)O, SC(O)O, NR^(c)C(O)O, OC(S)O, SC(S)O,NR^(c)C(S)O, OC(NR^(c))O, SC(NR^(c))O, NR^(c)C(NR^(c))O, OC(O)S, SC(O)S,NR^(c)C(O)S, OC(S)S, SC(S)S, NR^(c)C(S)S, OC(NR^(c))S, SC(NR^(c))S,NR^(c)C(NR^(c))S, OC(O)NR^(c), SC(O)NR^(c), NR^(c)C(O)NR^(c),OC(S)NR^(c), SC(S)NR^(c), NR^(c)C(S)NR^(c), OC(NR^(c))NR^(c),SC(NR^(c))NR^(c), NR^(c)C(NR^(c)NR^(c), S, SO, SO₂. NR^(c), SO₂NR^(c)and NR^(c)SO₂ wherein R^(c) is as hereinbefore defined.

The moiety R^(b) can be hydrogen or it can be a group selected fromcarbocyclic and heterocyclic groups having from 3 to 12 ring members(typically 3 to 10 and more usually from 5 to 10), and a C₁₋₈hydrocarbyl group optionally substituted as hereinbefore defined.Examples of hydrocarbyl, carbocyclic and heterocyclic groups are as setout above.

When R^(a) is O and R^(b) is a C₁₋₈ hydrocarbyl group, R^(a) and R^(b)together form a hydrocarbyloxy group. Preferred hydrocarbyloxy groupsinclude saturated hydrocarbyloxy such as alkoxy (e.g. C₁₋₆ alkoxy, moreusually C₁₋₄ alkoxy such as ethoxy and methoxy, particularly methoxy),cycloalkoxy (e.g. C₃₋₆ cycloalkoxy such as cyclopropyloxy,cyclobutyloxy, cyclopentyloxy and cyclohexyloxy) and cycloalkyalkoxy(e.g. C₃₋₆ cycloalkyl-C₁₋₂ alkoxy such as cyclopropylmethoxy).

The hydrocarbyloxy groups can be substituted by various substituents asdefined herein. For example, the alkoxy groups can be substituted byhalogen (e.g. as in difluoromethoxy and trifluoromethoxy), hydroxy (e.g.as in hydroxyethoxy), C₁₋₂ alkoxy (e.g. as in methoxyethoxy),hydroxy-C₁₋₂ alkyl (as in hydroxyethoxyethoxy) or a cyclic group (e.g. acycloalkyl group or non-aromatic heterocyclic group as hereinbeforedefined). Examples of alkoxy groups bearing a non-aromatic heterocyclicgroup as a substituent are those in which the heterocyclic group is asaturated cyclic amine such as morpholine, piperidine, pyrrolidine,piperazine, C₁₋₄-alkyl-piperazines, C₃₋₇-cycloalkyl-piperazines,tetrahydropyran or tetrahydrofuran and the alkoxy group is a C₁₋₄ alkoxygroup, more typically a C₁₋₃ alkoxy group such as methoxy, ethoxy orn-propoxy.

Alkoxy groups may be substituted by, for example, a monocyclic groupsuch as pyrrolidine, piperidine, morpholine and piperazine andN-substituted derivatives thereof such as N-benzyl, N—C₁₋₄ acyl andN—C₁₋₄ alkoxycarbonyl. Particular examples include pyrrolidinoethoxy,piperidinoethoxy and piperazinoethoxy.

When R^(a) is a bond and R^(b) is a C₁₋₈ hydrocarbyl group, examples ofhydrocarbyl groups R^(a)-R^(b) are as hereinbefore defined. Thehydrocarbyl groups may be saturated groups such as cycloalkyl and alkyland particular examples of such groups include methyl, ethyl andcyclopropyl. The hydrocarbyl (e.g. alkyl) groups can be substituted byvarious groups and atoms as defined herein. Examples of substitutedalkyl groups include alkyl groups substituted by one or more halogenatoms such as fluorine and chlorine (particular examples includingbromoethyl, chloroethyl, difluoromethyl, 2,2,2-trifluoroethyl andperfluoroalkyl groups such as trifluoromethyl), or hydroxy (e.g.hydroxymethyl and hydroxyethyl), C₁₋₈ acyloxy (e.g. acetoxymethyl andbenzyloxymethyl), amino and mono- and dialkylamino (e.g. aminoethyl,methylaminoethyl, dimethylaminomethyl, dimethylaminoethyl andtert-butylaminomethyl), alkoxy (e.g. C₁₋₂ alkoxy such as methoxy—as inmethoxyethyl), and cyclic groups such as cycloalkyl groups, aryl groups,heteroaryl groups and non-aromatic heterocyclic groups as hereinbeforedefined).

Particular examples of alkyl groups substituted by a cyclic group arethose wherein the cyclic group is a saturated cyclic amine such asmorpholine, piperidine, pyrrolidine, piperazine, C₁₋₄ alkyl-piperazines,C₃₋₇-cycloalkyl-piperazines, tetrahydropyran or tetrahydrofuran and thealkyl group is a C₁₋₄ alkyl group, more typically a C₁₋₃ alkyl groupsuch as methyl, ethyl or n-propyl. Specific examples of alkyl groupssubstituted by a cyclic group include pyrrolidinomethyl,pyrrolidinopropyl, morpholinomethyl, morpholinoethyl, morpholinopropyl,piperidinylmethyl, piperazinomethyl and N-substituted forms thereof asdefined herein.

Particular examples of alkyl groups substituted by aryl groups andheteroaryl groups include benzyl, phenethyl and pyridylmethyl groups.

When R^(a) is SO₂NR^(c), R^(b) can be, for example, hydrogen or anoptionally substituted C₁₋₈ hydrocarbyl group, or a carbocyclic orheterocyclic group. Examples of R^(a)-R^(b) where R^(a) is SO₂NR^(c)include aminosulphonyl, C₁₋₄ alkylaminosulphonyl and di-C₁₋₄alkylaminosulphonyl groups, and sulphonamides formed from a cyclic aminogroup such as piperidine, morpholine, pyrrolidine, or an optionallyN-substituted piperazine such as N-methyl piperazine.

Examples of groups R^(a)-R^(b) where R^(a) is SO₂ includealkylsulphonyl, heteroarylsulphonyl and arylsulphonyl groups,particularly monocyclic aryl and heteroaryl sulphonyl groups. Particularexamples include methylsulphonyl, phenylsulphonyl and toluenesulphonyl.

When R^(a) is NR^(c), R^(b) can be, for example, hydrogen or anoptionally substituted C₁₋₈ hydrocarbyl group, or a carbocyclic orheterocyclic group. Examples of R^(a)-R^(b) where R^(a) is NR^(c)include amino, C₁₋₄ alkylamino (e.g. methylamino, ethylamino,propylamino, isopropylamino, tert-butylamino), di-C₁₋₄ alkylamino (e.g.dimethylamino and diethylamino) and cycloalkylamino (e.g.cyclopropylamino, cyclopentylamino and cyclohexylamino).

Specific Embodiments of and Preferences for E, T, G, Q¹, Q², J¹, J² andR¹ to R¹⁰ T

In formula (I), T can be nitrogen or a group CR⁵ and J¹-J² can representa group selected from N═C(R⁶), (R⁷)C═N, (R⁸)N—C(O), (R⁸)₂C—C(O) and(R⁷)C═C(R⁶). Thus the bicyclic group can take the form of, for example:

-   -   a purine (T is N, J¹-J² is N═C(R⁶));    -   a 3H-imidazo[4,5-b]pyridine (T is CR⁵, J¹-J² is N═C(R⁶));    -   a 7H-pyrrolo[2,3-d]pyrimidine (T is N, J¹-J² is (R⁷)C═C(R⁶));    -   a 1H-pyrrolo[2,3-b]pyridine (T is CR⁵, J¹-J² is (R⁷)C═C(R⁶));    -   a 5,7-dihydro-pyrrolo[2,3-d]pyrimidin-6-one (T is N, J¹-J² is        (R⁸)₂C—C(O));    -   a 3H-[1,2,3]triazolo[4,5-d]pyrimidine (T is N, J¹-J² is N═N);    -   a 3H-[1,2,3]triazolo[4,5-b]pyridine (T is CR⁵, J¹-J² is N═N);    -   a 7,9-dihydro-purin-8-one (T is N, J¹-J² is (R⁸)N—C(O));    -   a 1H-pyrazolo[3,4-d]pyrimidine (T is N, J¹-J² is (R⁷)C═N); or    -   a pyrazolo[3,4-b]pyridine (T is CR⁵, J¹-J² is (R⁷)C═N).

R⁴

R⁴ is selected from hydrogen; halogen; C₁₋₆ hydrocarbyl optionallysubstituted by halogen, hydroxy or C₁₋₂ alkoxy; cyano; CONH₂; CONHR⁹;CF₃; NH₂; NHCOR⁹ and NHCONHR⁹. More typically, R⁴ is selected fromhydrogen, chlorine, fluorine and methyl, and preferably R⁴ is hydrogen.

R⁵

R⁵ is selected from hydrogen; halogen; C₁₋₆ hydrocarbyl optionallysubstituted by halogen, hydroxy or C₁₋₂ alkoxy; cyano; CONH₂; CONHR⁹;CF₃; NH₂; NHCOR⁹ and NHCONHR⁹. More typically, R⁵ is selected fromhydrogen, halogen, C₁₋₅ saturated hydrocarbyl, cyano and CF₃.Preferably, R⁵ is selected from hydrogen, chlorine, fluorine and methyl,and more preferably R⁵ is hydrogen.

R⁶

R⁶ is selected from hydrogen; halogen; C₁₋₆ hydrocarbyl optionallysubstituted by halogen, hydroxy or C₁₋₂ alkoxy; cyano; CONH₂; CONHR⁹;CF₃; NH₂; NHCOR⁹ and NHCONHR⁹. More typically R⁶ is selected fromhydrogen, chlorine, fluorine and methyl, and preferably R⁶ is hydrogen.

R⁷

R⁷ is selected from hydrogen; halogen; C₁₋₆ hydrocarbyl optionallysubstituted by halogen, hydroxy or C₁₋₂ alkoxy; cyano; CONH₂; CONHR⁹;CF₃; NH₂; NHCOR⁹ and NHCONHR⁹. More typically R⁷ is selected fromhydrogen, halogen, C₁₋₅ saturated hydrocarbyl, cyano and CF₃.Preferably, R⁷ is selected from hydrogen, chlorine, fluorine and methyl,and more preferably R⁷ is hydrogen.

R⁸

R⁸ is selected from hydrogen, halogen, C₁₋₅ saturated hydrocarbyl (e.g.alkyl), cyano, CONH₂, CONHR⁹, CF₃, NH₂, NHCOR⁹ and NHCONHR⁹. In oneembodiment, when attached to a nitrogen atom, R⁸ is selected fromhydrogen and C₁₋₅ saturated hydrocarbyl (e.g. alkyl) and more typicallyis selected from hydrogen, methyl and ethyl; and preferably is hydrogen.In another embodiment, when attached to a carbon atom, R⁸ is selectedfrom hydrogen, chlorine, fluorine, methyl, and ethyl; and preferably ishydrogen.

R⁹

R⁹ is phenyl or benzyl each optionally substituted as defined herein.Particular groups R⁹ are phenyl and benzyl groups that are unsubstitutedor are substituted with a solubilising group such as an alkyl or alkoxygroup bearing an amino, substituted amino, carboxylic acid or sulphonicacid group. Particular examples of solubilising groups includeamino-C₁₋₄-alkyl, mono-C₁₋₂-alkylamino-C₁₋₄-alkyl,di-C₁₋₂-alkylamino-C₁₋₄-alkyl, amino-C₁₋₄-alkoxy,mono-C₁₋₂-alkylamino-C₁₋₄-alkoxy, di-C₁₋₂-alkylamino-C₁₋₄-alkoxy,piperidinyl-C₁₋₄-alkyl, piperazinyl-C₁₋₄-alkyl, morpholinyl-C₁₋₄-alkyl,piperidinyl-C₁₋₄-alkoxy, piperazinyl-C₁₋₄-alkoxy andmorpholinyl-C₁₋₄-alkoxy.

Q¹ and Q²

Q¹ is a bond or a saturated hydrocarbon linker group containing from 1to 3 carbon atoms, wherein one of the carbon atoms in the linker groupmay optionally be replaced by an oxygen or nitrogen atom, or an adjacentpair of carbon atoms may be replaced by CONR^(q) or NR^(q)CO where R^(q)is hydrogen, C₁₋₄ alkyl or cyclopropyl, or R^(q) is a C₁₋₄ alkylenechain that links to R¹ or to another carbon atom of Q¹ to form a cyclicmoiety; and wherein the carbon atoms of the linker group Q¹ mayoptionally bear one or more substituents selected from fluorine andhydroxy.

Q² is a bond or a saturated hydrocarbon linker group containing from 1to 3 carbon atoms, wherein one of the carbon atoms in the linker groupmay optionally be replaced by an oxygen or nitrogen atom; and whereinthe carbon atoms of the linker group may optionally bear one or moresubstituents selected from fluorine and hydroxy, provided that thehydroxy group when present is not located at a carbon atom α withrespect to the G group.

In one embodiment, Q¹ and Q² are the same or different and are each abond or a saturated hydrocarbon linker group containing from 1 to 3carbon atoms, wherein one of the carbon atoms in the linker group mayoptionally be replaced by an oxygen or nitrogen atom; and wherein thecarbon atoms of the or each linker group Q¹ and Q² may optionally bearone or more substituents selected from fluorine and hydroxy, providedthat the hydroxy group when present is not located at a carbon atom αwith respect to the G² group.

In one group of compounds of the invention, at least one of Q¹ and Q²represents a bond. Within this group of compounds, one sub-groupconsists of compounds in which both of Q¹ and Q² represent a bond. Inanother sub-group, one of Q¹ and Q² represents a bond, and the otherrepresents a saturated hydrocarbon linker group containing from 1 to 3carbon atoms, wherein one of the carbon atoms in the linker group mayoptionally be replaced by an oxygen or nitrogen atom.

When Q¹ and/or Q² are saturated hydrocarbon groups, the hydrocarbongroups are typically alkylene groups such as (CH₂)_(n) where n is 1, 2or 3, one particular example being CH₂. One of the carbon atoms in thealkylene group Q¹ may optionally be replaced by, for example, an oxygenatom, and an example of such a group is CH₂—O—CH₂.

The carbon atoms of the linker groups Q¹ and Q² may optionally bear oneor more substituents selected from oxo, fluorine and hydroxy, providedthat the hydroxy group is not located at a carbon atom α with respect tothe NR²R³ group when present, and provided also that the oxo group islocated at a carbon atom α with respect to the NR²R³ group when present.Typically, the hydroxy group, if present, is located at a position βwith respect to G when G is other than hydrogen. In general, no morethan one hydroxy group will be present. Where fluorine atoms arepresent, they may be present in a difluoromethylene or trifluoromethylgroup, for example.

In one sub-group of compounds, Q¹ is a saturated hydrocarbon linkergroup containing from 1 to 3 carbon atoms, wherein an adjacent pair ofcarbon atoms is replaced by CONR^(q) or NR^(q)CO where R^(q) ishydrogen, C₁₋₄ alkyl or cyclopropyl, or R^(q) is a C₁₋₄ alkylene chainthat links to R¹ or to another carbon atom of Q¹ to form a cyclicmoiety. In one preferred embodiment, R^(q) is hydrogen. In anotherembodiment, R^(q) is C₁₋₄ alkyl or cyclopropyl, preferably methyl. In afurther embodiment, R^(q) is a C₁₋₄ alkylene chain that links to R¹ orto another carbon atom of Q¹ to form a cyclic moiety.

Examples of linker groups Q¹ containing CONR^(q) or NR^(q)CO are thegroups CH₂NHCO and CH₂N(Me)CO where the carbonyl group is attached to E.

Examples of linker groups Q¹ containing CONR^(q) or NR^(q)CO, whereR^(q) is a C₁₋₄ alkylene chain that links to another carbon atom of Q¹to form a cyclic moiety, are groups represented by the formula:

where * represents the point of attachment to the moiety E, q″ is 0, 1or 2, and the point of attachment to R¹ is indicated by the letter “c”.

Examples of linker groups Q¹ containing CONR^(q) or NR^(q)CO, whereR^(q) is a C₁₋₄ alkylene chain that links to R¹ to form a cyclic moiety,are groups represented by the formula:

where q is as defined herein and R¹ is an aryl or heteroaryl group.Particular examples of moieties R¹-Q¹ of this type include1,2,3,4-tetrahydroisoquinolin-2-ylcarbonyl.

It will be appreciated that that when an oxo group is present at thecarbon atom adjacent an NR²R³ group, the compound of the formula (I)will be an amide.

In one embodiment of the invention, no fluorine atoms are present in thelinker groups Q¹ and/or Q².

In another embodiment of the invention, no hydroxy groups are present inthe linker groups Q¹ and/or Q².

In a further embodiment, no oxo group is present in the linker groups Q¹and/or Q².

In one group of compounds of the formula (I) neither hydroxy groups norfluorine atoms are present in the linker groups Q¹ and/or Q², e.g. thelinker groups Q¹ and/or Q² are unsubstituted.

In another group of compounds of the invention, the linker group Q² canhave a branched configuration at the carbon atom attached to the NR²R³group, when present. For example, the carbon atom attached to the NR²R³group can be attached to a pair of gem-dimethyl groups.

Q¹ and Q² may be attached to the same atom of group E, or to differentatoms. In one embodiment, Q¹ and Q² are attached to the same atom (i.e.a carbon atom) of group E.

G

The moiety G is selected from hydrogen, NR²R³, OH and SH with theproviso that when E is aryl or heteroaryl and Q² is a bond, then G ishydrogen. Thus, in the compounds of formula (I), an amino group NR²R³ oran SH or OH group are not directly linked to E when E is an aryl orheteroaryl group.

In one embodiment, G is hydrogen.

Preferably at least one of R¹ and G is other than hydrogen.

In another embodiment, G is selected from NR²R³, OH and SH. Within thisembodiment, one particular sub-group of compounds is the group in whichG is NR²R³.

Within the sub-group of compounds in which G is NR²R³, R² and R³ can beindependently selected from hydrogen; C₁₋₄ hydrocarbyl and C₁₋₄ acylwherein the hydrocarbyl and acyl groups are optionally substituted byone or more substituents selected from fluorine, hydroxy, cyano, amino,methylamino, dimethylamino, methoxy and a monocyclic or bicyclic aryl orheteroaryl group;

In one group of compounds, R² and R³ are independently selected fromhydrogen; C₁₋₄ hydrocarbyl and C₁₋₄ acyl wherein the hydrocarbyl andacyl groups are optionally substituted by one or more substituentsselected from fluorine, hydroxy, amino, methylamino, dimethylamino,methoxy and a monocyclic or bicyclic aryl or heteroaryl group.

Within this group of compounds are the compounds wherein R² and R³ areindependently selected from hydrogen; C₁₋₄ hydrocarbyl and C₁₋₄ acylwherein the hydrocarbyl and acyl groups are each optionally substitutedby a monocyclic or bicyclic aryl or heteroaryl group.

Also within this group of compounds is the sub-group of compounds of theinvention wherein R² and R³ are independently selected from hydrogen,C₁₋₄ hydrocarbyl and C₁₋₄ acyl.

In each of the foregoing groups and sub-groups of compounds, thehydrocarbyl group forming part of NR²R³ typically is an alkyl group,more usually a C₁, C₂ or C₃ alkyl group, for example a methyl group.

In a particular sub-group of compounds, R² and R³ are independentlyselected from hydrogen and methyl and hence NR²R³ can be an amino,methylamino or dimethylamino group.

In one embodiment, NR²R³ is an amino group. In another particularembodiment, NR²R³ is a methylamino group.

In another group of compounds, R² and R³ together with the nitrogen atomto which they are attached form a saturated monocyclic heterocyclicgroup having 4-7 ring members and optionally containing a secondheteroatom ring member selected from O and N.

In another group of compounds, NR²R³ and a carbon atom of linker groupQ² to which it is attached from a cyano group.

In a further group of compounds, NR²R³ is as hereinbefore defined exceptthat NR²R³ and a carbon atom of linker group Q² to which it is attachedmay not form a cyano group.

The saturated monocyclic ring can be an azacycloalkyl group such as anazetidine, pyrrolidine, piperidine or azepane ring, and such rings aretypically unsubstituted.

Alternatively, the saturated monocyclic ring can contain an additionalheteroatom selected from O and N, and examples of such groups includemorpholine and piperazine. Where an additional N atom is present in thering, this can form part of an NH group or an N—C₁₋₄alkyl group such asan N-methyl, N-ethyl, N-propyl or N-isopropyl group.

In a further group of compounds, one of R² and R³ together with thenitrogen atom to which they are attached and one or more atoms from thelinker group Q² form a saturated monocyclic heterocyclic group having4-7 ring members and optionally containing a second heteroatom ringmember selected from O and N.

R¹

The group R¹ is hydrogen or a heteroaryl group, wherein the aryl orheteroaryl group may be selected from the list of such groups set out inthe section headed General Preferences and Definitions.

In one sub-group of compounds, R¹ is hydrogen.

In another sub-group of compounds, R¹ is an aryl or heteroaryl group.

When R¹ is aryl or heteroaryl, it can be monocyclic or bicyclic and, inone particular embodiment, is monocyclic. Particular examples ofmonocyclic aryl and heteroaryl groups are six membered aryl andheteroaryl groups containing up to 2 nitrogen ring members, and fivemembered heteroaryl groups containing up to 3 heteroatom ring membersselected from O, S and N.

Examples of such groups include phenyl, naphthyl, thienyl, furan,pyrimidine and pyridine, with phenyl being presently preferred.

The aryl or heteroaryl group R¹ can be unsubstituted or substituted byup to 5 substituents, and examples of substituents are those listed inany one of groups R¹⁰R^(10a), R^(10b) and R^(10c) above.

In one embodiment, the aryl or heteroaryl group R¹ is unsubstituted.

In another embodiment, the aryl or heteroaryl group R¹ is substituted byone or more substituents selected from those listed in any one of groupsR¹⁰R^(10a), R^(10b) and R^(10c) above.

One particular group of substituents for the aryl or heteroaryl group R¹consists of hydroxy; C₁₋₄ acyloxy; fluorine; chlorine; bromine;trifluoromethyl; cyano; C₁₋₄ hydrocarbyloxy and C₁₋₄ hydrocarbyl eachoptionally substituted by one or more C₁₋₂ alkoxy, halogen, hydroxy oroptionally substituted phenyl or pyridyl groups; C₁₋₄ acylamino;benzoylamino; pyrrolidinocarbonyl; piperidinocarbonyl;morpholinocarbonyl; piperazinocarbonyl; five and six membered heteroarylgroups containing one or two heteroatoms selected from N, O and S, theheteroaryl groups being optionally substituted by one or more C₁₋₄ alkylsubstituents; optionally substituted phenyl; optionally substitutedpyridyl; and optionally substituted phenoxy; wherein the optionalsubstituent for the phenyl, pyridyl and phenoxy groups are 1, 2 or 3substituents selected from C₁₋₂ acyloxy, fluorine, chlorine, bromine,trifluoromethyl, cyano, C₁₋₂ hydrocarbyloxy and C₁₋₂ hydrocarbyl eachoptionally substituted by methoxy or hydroxy.

Another particular group of substituents for the aryl (e.g. phenyl) orheteroaryl group R¹ consists of hydroxy; C₁₋₄ acyloxy; fluorine;chlorine; bromine; trifluoromethyl; cyano; C₁₋₄ hydrocarbyloxy and C₁₋₄hydrocarbyl each optionally substituted by C₁₋₂ alkoxy or hydroxy; C₁₋₄acylamino; benzoylamino; pyrrolidinocarbonyl; piperidinocarbonyl;morpholinocarbonyl; piperazinocarbonyl; five and six membered heteroarylgroups containing one or two heteroatoms selected from N, O and S, theheteroaryl groups being optionally substituted by one or more C₁₋₄ alkylsubstituents; phenyl; pyridyl; and phenoxy wherein the phenyl, pyridyland phenoxy groups are each optionally substituted with 1, 2 or 3substituents selected from C₁₋₂ acyloxy, fluorine, chlorine, bromine,trifluoromethyl, cyano, C₁₋₂ hydrocarbyloxy and C₁₋₂ hydrocarbyl eachoptionally substituted by methoxy or hydroxy.

Although up to 5 substituents may be present, more typically there are0, 1, 2, 3 or 4 substituents, preferably 0, 1, 2 or 3, and morepreferably 0, 1 or 2.

In one embodiment, R¹ is unsubstituted (e.g. is an unsubstituted phenylgroup) or substituted (e.g. is a substituted phenyl group) by up to 5substituents selected from hydroxy; C₁₋₄ acyloxy; fluorine; chlorine;bromine; trifluoromethyl; trifluoromethoxy; difluoromethoxy; benzyloxy;cyano; C₁₋₄ hydrocarbyloxy and C₁₋₄ hydrocarbyl each optionallysubstituted by C₁₋₂ alkoxy or hydroxy.

In another embodiment, the group R¹ is unsubstituted (e.g. is anunsubstituted phenyl group) or substituted (e.g. is a substituted phenylgroup) substituted by up to 5 substituents selected from hydroxy; C₁₋₄acyloxy; fluorine; chlorine; bromine; trifluoromethyl; cyano; C₁₋₄hydrocarbyloxy and C₁₋₄ hydrocarbyl each optionally substituted by C₁₋₂alkoxy or hydroxy.

In another embodiment, the group R¹ can have one or two substituentsselected from fluorine, chlorine, trifluoromethyl, trifluoromethoxy,difluoromethoxy, benzyloxy, methyl and methoxy.

In a further embodiment, the group R¹ can have one or two substituentsselected from fluorine, chlorine, trifluoromethyl, trifluoromethoxy,difluoromethoxy, benzyloxy, tert-butyl, methyl and methoxy.

For example, R¹ can have one or two substituents selected from fluorine,chlorine, trifluoromethyl, methyl and methoxy.

When R¹ is a phenyl group, particular examples of substituentcombinations include mono-chlorophenyl and dichlorophenyl. Furtherexamples include benzyloxyphenyl, trifluoromethoxyphenyl,tert-butylphenyl, methoxyphenyl, fluoro-chlorophenyl, difluorophenyl,and trifluoromethylphenyl.

In one sub-group of compounds, the group R¹ is a phenyl group having asubstituent at the para position selected from fluorine, chlorine,trifluoromethyl, trifluoromethoxy, difluoromethoxy, benzyloxy, methyland methoxy.

In another sub-group of compounds, the group R¹ is a phenyl group havinga tert-butyl substituent at the para position.

In another sub-group of compounds, the group R¹ is a phenyl group havinga substituent at the ortho position selected from fluorine, chlorine,trifluoromethyl, trifluoromethoxy, difluoromethoxy, methyl and methoxy,and optionally a second substituent at the meta or para positionselected from the group R¹ is a phenyl group having a substituent at thepara position selected from fluorine, chlorine, trifluoromethyl,trifluoromethoxy, difluoromethoxy, methyl and methoxy.

When R¹ is a six membered aryl or heteroaryl group, a substituent mayadvantageously be present at the para position on the six-membered ring.Where a substituent is present at the para position, it is preferablylarger in size than a fluorine atom.

Particular examples of the group R¹ are shown in Table 1 below, thepoint of attachment to Q¹ (or E when Q¹ is a bond) being indicated bymeans of an asterisk.

A1

A2

A3

A4

A5

A6

A7

A8

A9

A10

A11

A12

A13

A14

A15

A16

A17

A18

A19

A20

A21

A22

A23

A24

A25

A26

A27

A28

A29

One set of preferred groups R¹ includes groups A2, A4 and A5 in Table 1.

Another set of preferred groups includes groups A2, A4, A5, A10, A11,A13, A14, A15, A16, A17, A18, A19 and A19.

E

In formula (I), E is a monocyclic carbocyclic or heterocyclic group of 5or 6 ring members wherein the heterocyclic group contains up to 3heteroatoms selected from O, N and S.

The carbocyclic or heterocyclic group E can be aromatic or non-aromatic.

In one embodiment, the carbocyclic or heterocyclic group E isnon-aromatic.

In another embodiment, the carbocyclic or heterocyclic group E isaromatic.

When E is an aromatic group, i.e. an aryl or heteroaryl group, the groupcan be selected from the examples of such groups set out in the GeneralPreferences and Definitions section above.

Particular aromatic cyclic groups E are aryl and heteroaryl groupscontaining a six membered aromatic or heteroaromatic ring such as aphenyl, pyridine, pyrazine, pyridazine or pyrimidine ring, moreparticularly a phenyl, pyridine, pyrazine or pyrimidine ring, and morepreferably a pyridine or phenyl ring.

Examples of non-aromatic monocyclic are as set out in the GeneralPreferences and Definitions section above.

Particular examples of groups include cycloalkanes such as cyclohexaneand cyclopentane, and nitrogen-containing rings such as piperidine,pyrrolidine, piperidine, piperazine and piperazone.

One particular non-aromatic monocyclic group is a piperidine group andmore particularly a piperidine group wherein the nitrogen atom of thepiperidine ring is attached to the bicyclic group.

The moieties Q¹ and Q² can be attached to the same carbon atom in thegroup E or they can be attached to separate atoms. It will beappreciated that when the group E is aromatic, Q¹ and Q² cannot beattached to the same carbon atom in the group E but may be, for example,attached to adjacent carbon atoms.

In one embodiment, E is non-aromatic and Q¹ and Q² are attached to thesame carbon atom in the group E.

In another embodiment, Q¹ and Q² are attached to different atoms in thegroup E.

It is preferred that the group Q² and the bicyclic group are attached tothe group E in a meta or para relative orientation; i.e. Q² and thebicyclic group are not attached to adjacent ring members of the group E.Examples of groups such groups E include 1,4-phenylene, 1,3-phenylene,2,5-pyridylene and 2,4-pyridylene, 1,4-piperidinyl, 1,4-piperindonyl,1,4-piperazinyl, and 1,4-piperazonyl.

The groups E can be unsubstituted or can have up to 4 substituents R¹¹which may be selected from the group R¹⁰ as hereinbefore defined. Moretypically however, the substituents R¹¹ are selected from hydroxy; oxo(when E is non-aromatic); halogen (e.g. chlorine and bromine);trifluoromethyl; cyano; C₁₋₄ hydrocarbyloxy optionally substituted byC₁₋₂ alkoxy or hydroxy; and C₁₋₄ hydrocarbyl optionally substituted byC₁₋₂ alkoxy or hydroxy.

Typically, there are 0-3 substituents, more usually 0-2 substituents,for example 0 or 1 substituent. In one embodiment, the group E isunsubstituted. In one particular group of compounds of the invention, Eis a group:

where G³ is selected from C, CH, CH₂, N and NH; and G⁴ is selected fromN and CH.

Particular examples of the group E, together with their points ofattachment to the groups Q¹ and Q² (^(a)) and the bicyclic group (*) areshown in Table 2 below.

TABLE 2

B1

B2

B3

B4

B9

B10

B11

B12

One preferred group E is group B9.

Particular and Preferred Sub-Groups of the Formula (I)

One sub-group of compounds of the formula (I) has the general formula(II):

wherein R¹, R⁴, Q¹, Q², T, J¹, J² and G are as defined herein in respectof formula (I) and sub-groups, examples and preferences thereof. WithinFormula (II), particular compounds are those in which Q¹ is a bond or aC₁₋₂ alkylene group and Q² is a bond or a methylene group. Preferably R¹is an aryl or heteroaryl group.

Within Formula (II), one sub-group of compounds has the general formula(IIa):

or a salt, solvate tautomer or N-oxide thereof;wherein R¹ is an aryl or heteroaryl group;G is selected from NR²R³, OH and SH;and R⁴, Q, Q², T, J¹ and J² are as defined herein.

In formulae (II) and (IIa), preferably G is NR²R³ and more preferably Gis NH₂ or NHMe.

In formulae (II) and (IIa) and embodiments thereof, the group R¹ ispreferably an optionally substituted aryl or heteroaryl group, andtypically a monocyclic aryl or heteroaryl group of 5 or 6 ring members.Particular aryl and heteroaryl groups are phenyl, pyridyl, furanyl andthienyl groups, each optionally substituted. Optionally substitutedphenyl groups are particularly preferred.

Alternatively, the group R¹ can be, for example, an optionallysubstituted naphthyl group, for example an optionally substituted1-naphthyl group. One particular example of such a group isunsubstituted 1-naphthyl.

The aryl or heteroaryl group R¹ (e.g. a phenyl, pyridyl, furanyl orthienyl group) can be unsubstituted or substituted by up to 5substituents, and examples of substituents are those listed above ingroups R¹⁰, R^(10a), R^(10b) and R^(10c).

Particular sub-groups of compounds of the formulae (II) or (IIa) consistof compounds in which R¹ is unsubstituted phenyl or, more preferably;phenyl bearing 1 to 3 (and more preferably 1 or 2) substituents selectedfrom hydroxy; C₁₋₄ acyloxy; fluorine; chlorine; bromine;trifluoromethyl; cyano; C₁₋₄ hydrocarbyloxy and C₁₋₄ hydrocarbyl groupswherein the C₁₋₄ hydrocarbyloxy and C₁₋₄ hydrocarbyl groups are eachoptionally substituted by one or more C₁₋₂ alkoxy, halogen, hydroxy oroptionally substituted phenyl or pyridyl groups; C₁₋₄ acylamino;benzoylamino; pyrrolidinocarbonyl; piperidinocarbonyl;morpholinocarbonyl; piperazinocarbonyl; five and six membered heteroarylgroups containing one or two heteroatoms selected from N, O and S, theheteroaryl groups being optionally substituted by one or more C₁₋₄ alkylsubstituents; optionally substituted phenyl; optionally substitutedpyridyl; and optionally substituted phenoxy; wherein the optionalsubstituent for the phenyl, pyridyl and phenoxy groups are 1, 2 or 3substituents selected from C₁₋₂ acyloxy, fluorine, chlorine, bromine,trifluoromethyl, cyano, and C₁₋₂ hydrocarbyloxy and C₁₋₂-hydrocarbylgroups wherein the C₁₋₂ hydrocarbyloxy and C₁₋₂ hydrocarbyl groups areeach optionally substituted by methoxy or hydroxy.

More particular sub-groups of compounds within formulae (II) and (IIa)consist of compounds wherein R¹ is unsubstituted phenyl or, morepreferably, phenyl bearing 1 to 3 (and more preferably 1 or 2)substituents independently selected from hydroxy; C₁₋₄ acyloxy;fluorine; chlorine; bromine; trifluoromethyl; cyano; C₁₋₄ alkoxy or C₁₋₄alkyl groups wherein the C₁₋₄ alkoxy and C₁₋₄ alkyl groups are eachoptionally substituted by one or more fluorine atoms or by C₁₋₂ alkoxy,hydroxy or optionally substituted phenyl; C₁₋₄ acylamino; benzoylamino;pyrrolidinocarbonyl; piperidinocarbonyl; morpholinocarbonyl;piperazinocarbonyl; optionally substituted phenyl; optionallysubstituted pyridyl; and optionally substituted phenoxy wherein theoptionally substituted phenyl, pyridyl and phenoxy groups are eachoptionally substituted with 1, 2 or 3 substituents selected from C₁₋₂acyloxy, fluorine, chlorine, bromine, trifluoromethyl, cyano, C₁₋₂hydrocarbyloxy and C₁₋₂ hydrocarbyl each optionally substituted bymethoxy or hydroxy.

Although up to 5 substituents may be present, more typically there are0, 1, 2, 3 or 4 substituents, preferably 0, 1, 2 or 3, and morepreferably 0, 1 or 2.

In one embodiment within each of formulae (II) and (IIa), R¹ isunsubstituted phenyl or a phenyl group substituted by 1 or 2substituents independently selected from hydroxy; C₁₋₄ acyloxy;fluorine; chlorine; bromine; trifluoromethyl; trifluoromethoxy;difluoromethoxy; benzyloxy; cyano; C₁₋₄ hydrocarbyloxy and C₁₋₄hydrocarbyl each optionally substituted by C₁₋₂ alkoxy or hydroxy.

More preferably, the group R¹ is a substituted phenyl group bearing 1 or2 substituents independently selected from fluorine; chlorine;trifluoromethyl; trifluoromethoxy; difluoromethoxy; cyano; methoxy,ethoxy, i-propoxy, methyl, ethyl, propyl, isopropyl, tert-butyl andbenzyloxy.

In one sub-group of compounds within each of formulae (II) and (IIa),the group R¹ is a phenyl group having a substituent at the para positionselected from fluorine, chlorine, trifluoromethyl, trifluoromethoxy,difluoromethoxy, benzyloxy, methyl, tert-butyl and methoxy, andoptionally a second substituent at the ortho- or meta-position selectedfrom fluorine, chlorine or methyl. Within this sub-group, the phenylgroup can be monosubstituted. Alternatively, the phenyl group can bedisubstituted.

In a particular sub-group of compounds within each of formulae (II) and(IIa), the group R¹ is a monosubstituted phenyl group having atert-butyl substituent at the para position.

In another particular sub-group of compounds within each of formulae(II) and (IIa), the group R¹ is a monosubstituted phenyl group having achlorine substituent at the para position.

In a further sub-group of compounds within each of formulae (II) and(IIa), R¹ is a dichlorophenyl group, particular examples of which are2,4-dichlorophenyl, 2,5-dichlorophenyl, 3,4-dichlorophenyl and2,3-dichlorophenyl.

In each of formulae (II) and (IIa) and the above embodiments, sub-groupsand examples thereof:

-   -   T is preferably N; and/or    -   R⁴ is hydrogen; and/or    -   J¹-J² represents a group selected from N═CH, HN—C(O), (Me)NC(O),        (Et)NC(O) and HC═CH; and/or    -   Q¹ is a bond or a C₁₋₂ alkylene group and Q² is a bond or a        methylene group; and/or    -   G is NR²R³ and more preferably G is NH₂ or NHMe.

Another sub-group of compounds within Formula (II) has the generalformula (III):

wherein R², R³, R⁴, T, J¹ and J² are as defined herein in respect offormula (I) and sub-groups, examples and preferences thereof.

Another sub-group of compounds within formula (II) has the generalformula (IV):

wherein m is 0, 1 or 2; m′ is 0 or 1 provided that the sum of m and m′is in the range 0 to 2; n is 0 or 1; p is 0, 1, 2 or 3; R^(x) and R^(y)are the same or different and each is selected from hydrogen, methyl andfluorine; R¹² is CN or NR²R³ and each R¹³ is independently selected fromR¹⁰, R^(10a), R^(10b) and R^(10c) wherein J¹, J², T, R², R³, R⁴, R¹⁰,R^(10a), R^(10b) and R^(10c) are as defined herein.

In formula (IV), m is preferably 0 or 1. When m′ is 0, more preferably mis 1. When m′ is 1, preferably m is 0.

In one group of compounds n is 0. In another group of compounds, n is 1.

Preferably p is 0, 1 or 2 and R¹³ is selected from hydroxy; C₁₋₄acyloxy; fluorine; chlorine; bromine; trifluoromethyl; trifluoromethoxy;difluoromethoxy; benzyloxy; cyano; C₁₋₄ hydrocarbyloxy and C₁₋₄hydrocarbyl each optionally substituted by C₁₋₂ alkoxy or hydroxy.

More preferably, R¹³ is selected from fluorine; chlorine;trifluoromethyl; trifluoromethoxy; difluoromethoxy; cyano; methoxy,ethoxy, i-propoxy, methyl, ethyl, propyl, isopropyl, tert-butyl andbenzyloxy.

For example the phenyl group may have a substituent R¹³ at the paraposition selected from fluorine, chlorine, trifluoromethyl,trifluoromethoxy, difluoromethoxy, benzyloxy, methyl, tert-butyl andmethoxy, and optionally a second substituent at the ortho- ormeta-position selected from fluorine, chlorine or methyl. Within thissub-group, the phenyl group can be monosubstituted. Alternatively, thephenyl group can be disubstituted.

In another sub-group of compounds, p is 1 and the substituent R¹³ is atert-butyl substituent at the para position.

In another sub-group of compounds, p is 1 and the substituent R¹³ is achlorine substituent at the para position.

In another sub-group of compounds, p is 2 and the phenyl group is adichlorophenyl group, particular examples of which are2,4-dichlorophenyl, 2,5-dichlorophenyl, 3,4-dichlorophenyl and2,3-dichlorophenyl.

In one sub-group of compounds within formula (IV), R¹² is NR²R³ and morepreferably R¹² is selected from NH₂, NHMe and NMe₂, with NH₂ beingparticularly preferred.

One particular sub-group of compounds within formula (IV) can berepresented by the formula (V):

wherein J¹, J², R^(x), R^(y), R⁴, p and R^(10c) are as defined herein,and R^(w) is hydrogen or methyl. In one embodiment, R^(w) is hydrogen.In another embodiment, R^(w) is methyl. Preferably, p is 0, 1 or 2 andeach substituent R^(10c) (when p is 1 or 2) is selected from thesubstituents listed above in respect of R¹³ and its embodiments,sub-groups and examples.

In formulae (IV) and (V), R^(x) and R^(y) may both be hydrogen.

Alternatively, R^(x) and R^(y) may both be methyl, or may both befluorine, or one of R^(x) and R^(y) may be hydrogen and the other may bemethyl or fluorine.

Another sub-group of compounds within formula (II) can be represented byformula (VI)

wherein R^(q) is hydrogen or methyl and R^(10c), R⁴, R^(w), J¹ and J²are as defined herein.

Preferably, p is 0, 1 or 2 and each substituent R^(10c) (when p is 1 or2) is selected from the substituents listed above in respect of R¹³ andits embodiments, sub-groups and examples.

In one group of compounds, R^(q) is hydrogen. In another group ofcompounds, R^(q) is methyl.

In one embodiment, R^(w) is hydrogen. In another embodiment, R^(w) ismethyl.

Compounds of formulae (V) and (VI) show selectivity as inhibitors of PKBrelative to PKA.

Particular compounds within formulae (V) and (VI) are those wherein R⁴is hydrogen.

In formulae (V) and (VI), the moiety J¹-J² is preferably selected fromN═CH, CH═CH, HN—C(O), (Me)NC(O) and (Et)NC(O), and more preferably fromN═CH and CH═CH.

In one particularly preferred group of compounds within formulae (V) and(VI), the moiety J¹-J² is CH═CH.

In each of formulae (V) and (VI), one group of preferred substituentsR^(10c) consists of chlorine, fluorine, methyl, ethyl, isopropyl,methoxy, difluoromethoxy, trifluoromethoxy, trifluoromethyl, tert-butyl,cyano and benzyloxy.

In each of formulae (V) and (VI), a further group of preferredsubstituents R^(10c) consists of chlorine, fluorine, methyl, methoxy,difluoromethoxy, trifluoromethoxy, trifluoromethyl, cyano and benzyloxy.

In formulae (V) and (VI), p is preferably 1 or 2.

In one embodiment, p is 1.

In another embodiment, p is 2.

When p is 1, the phenyl ring can be 2-substituted, or 3-substituted, or4-substituted.

Particular examples of groups wherein p is 1 are the groups A2, A3, A5,A6, A8, A9, A10, A11, A12, A15, A18 and A19 in Table 1 above. Morepreferred groups are groups A2, A5, A10, A11, A15, A18 and A19 in Table1.

When p is 2, the phenyl ring can be, for example, 2,3-disubstituted,2,4-disubsubstituted, or 2,5-disubstituted.

Particular examples of groups wherein p is 2 are the groups A4, A7, A13,A14, A16, A17 and A20 in Table 1.

Another sub-group of compounds of the invention can be represented bythe formula (VII):

wherein Ar is a 5- or 6-membered monocyclic aryl or heteroaryl grouphaving up to 2 heteroatom ring members selected from O, N and S andbeing optionally substituted by one or two substituents selected fromfluorine, chlorine, methyl and methoxy; R^(10d) is a substituentselected from fluorine, chlorine, methyl, trifluoromethyl,trifluoromethoxy and methoxy; r is 0, 1 or 2 (more typically 0 or 1);and T, Q¹, Q², NR²R³, R⁴, and J¹-J² are as defined herein.

In formula (VII), particular 5- or 6-membered monocyclic aryl orheteroaryl groups Ar can be selected from phenyl, pyridyl, furyl andthienyl, each optionally substituted as defined herein. One particularmonocyclic aryl group is optionally substituted phenyl, withunsubstituted phenyl being a particular example.

Within formula (VII), preferred compounds are those compounds whereinNR²R³ is selected from NH₂, NHMe and NMe₂ (with NH₂ being particularlypreferred); and/or R⁴ is hydrogen or methyl (more preferably hydrogen);and/or T is CH or N; and/or Q¹ is selected from CH₂ and CH₂NHCO (whereinthe carbonyl group is attached to the piperidine ring); and/or Q² isselected from CH₂ and a bond (and more preferably is a bond); and/orJ¹-J² is selected from CH═N and CH═CH.

For the avoidance of doubt, it is to be understood that each general andspecific preference, embodiment and example of the groups R¹ may becombined with each general and specific preference, embodiment andexample of the groups R² and/or R³ and/or R⁴ and/or R⁵ and/or R⁶ and/orR⁷ and/or R⁸ and R⁹ and/or R¹⁰ and/or R¹¹ and J¹-J² and/or T and/or Q¹and/or Q² and that all such combinations are embraced by thisapplication.

The various functional groups and substituents making up the compoundsof the formula (I) are typically chosen such that the molecular weightof the compound of the formula (I) does not exceed 1000. More usually,the molecular weight of the compound will be less than 750, for exampleless than 700, or less than 650, or less than 600, or less than 550.More preferably, the molecular weight is less than 525 and, for example,is 500 or less.

Particular compounds of the invention are as illustrated in the examplesbelow and include:

-   methyl-[1-(9H-purin-6-yl)-piperidin-4-yl]-amine;-   benzyl-[1-(9H-purin-6-yl)-piperidin-4-yl]-amine;-   1-(9H-purin-6-yl)piperidin-4-ylamine;-   6-(4-aminopiperidin-1-yl)-7,9-dihydropurin-8-one;-   6-(4-benzyl-4-hydroxypiperidin-1-yl)-7,9-dihydropurin-8-one;-   6-(piperazin-1-yl)-7,9-dihydropurin-8-one;-   (3S)-6-(3-benzyloxymethylpiperazin-1-yl)-7,9-dihydropurin-8-one;-   6-(4-phenethylaminopiperidin-1-yl)-7,9-dihydro-purin-8-one;-   6-[4-(2-chlorobenzylamino)-piperidin-1-yl]-7,9-dihydro-purin-8-one;-   6-[4-(3-chlorobenzylamino)-piperidin-1-yl]-7,9-dihydro-purin-8-one;-   1-(1H-pyrazolo[3,4-d]pyrimidin-4-yl)-piperidin-4-ylamine;-   1-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-piperidin-4-ylamine;-   1-(1H-pyrrolo[2,3-b]pyridin-4-yl)-piperidin-4-ylamine;-   C-[4-(4-chloro-phenyl)-1-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-piperidin-4-yl]-methylamine;-   C-[4-(4-chloro-phenyl)-1-(9H-purin-6-yl)-piperidin-4-yl]-methylamine;-   4-benzyl-1-(9H-purin-6-yl)piperidin-4-ylamine;-   4-(4-chlorobenzyl)-1-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)piperidin-4-ylamine;-   4-(4-chlorobenzyl)-1-(9H-purin-6-yl)piperidin-4-yl amine;-   C-[4-(4-chlorobenzyl)-1-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)piperidin-4-yl]methylamine;-   6-[4-aminomethyl-4-(4-chlorophenyl)piperidin-1-yl]-7,9-dihydropurin-8-one;-   C-[4-(4-chlorophenyl)-1-(1H-pyrrolo[2,3-b]pyridin-4-yl)piperidin-4-yl]methylamine;-   6-[4-aminomethyl-4-(4-chlorophenyl)piperidin-1-yl]-7-benzyl-7,9-dihydro-purin-8-one;-   6-[4-aminomethyl-4-(4-chlorophenyl)piperidin-1-yl]-7-ethyl-7,9-dihydro-purin-8-one;-   C-[4-(4-chlorobenzyl)-1-(9H-purin-6-yl)piperidin-4-yl]methylamine;-   4-(4-chlorophenyl)-1-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)piperidine-4-carbonitrile;-   4-(4-chlorophenyl)-1-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)piperidin-4-ylamine;-   C-[4-(3-chlorophenyl)-1-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)piperidin-4-yl]methylamine;-   C-[4-(3-chlorophenyl)-1-(9H-purin-6-yl)piperidin-4-yl]methylamine;-   C-[4-(3,4-dichlorophenyl)-1-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)piperidin-4-yl]methylamine;-   C-[4-(3,4-dichlorophenyl)-1-(9H-purin-6-yl)piperidin-4-yl]methylamine;-   C-[1-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-4-trifluoromethoxyphenyl)piperidin-4-yl]methylamine;-   C-[1-(9H-purin-6-yl)-4-(4-trifluoromethoxyphenyl)piperidin-4-yl]methylamine;-   1-(5-phenyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-piperidin-4-ylamine;-   C-[1-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-4-(4-trifluoromethylphenyl)piperidin-4-yl]methylamine;-   C-[1-(9H-purin-6-yl)-4-(4-trifluoromethylphenyl)piperidin-4-yl]methylamine;-   C-[1-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-4-(3-trifluoromethylphenyl)piperidin-4-yl]methylamine;-   C-[1-(9H-purin-6-yl)-4-(3-trifluoromethylphenyl)piperidin-4-yl]methylamine;-   C-[4-(3,4-difluorophenyl)-1-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)piperidin-4-yl]methylamine;-   C-[4-(3,4-difluorophenyl)-1-(9H-purin-6-yl)piperidin-4-yl]methylamine;-   C-[4-(4-methoxyphenyl)-1-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)piperidin-4-yl]methylamine;-   C-[4-(4-methoxyphenyl)-1-(9H-purin-6-yl)piperidin-4-yl]methylamine;-   C-[4-(4-benzyloxyphenyl)-1-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)piperidin-4-yl]methylamine;-   C-[4-(4-benzyloxyphenyl)-1-(9H-purin-6-yl)piperidin-4-yl]methylamine;-   [4-(4-chloro-phenyl)-1-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-piperidin-4-ylmethyl]-methyl-amine;-   [4-(4-chlorophenyl)-1-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-piperidin-4-ylmethyl]-isopropylamine;-   [4-(4-chlorobenzyl)-1-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-piperidin-4-yl]-dimethylamine;-   C-[4-(3,4-dichlorobenzyl)-1-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)piperidin-4-yl]methylamine;-   C-[4-(3,4-dichlorobenzyl)-1-(9H-purin-6-yl)piperidin-4-yl]methylamine;-   C-[1-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-4-(4-trifluoromethoxybenzyl)piperidin-4-yl]methylamine;-   C-[1-(9H-purin-6-yl)-4-(4-trifluoromethoxybenzyl)piperidin-4-yl]methylamine;-   4-(3,4-dichlorobenzyl)-1-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)piperidin-4-ylamine;-   4-(3,4-dichlorobenzyl)-1-(9H-purin-6-yl)piperidin-4-yl amine;-   1-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-4-(4-trifluoromethoxybenzyl)piperidin-4-ylamine;-   1-(9H-purin-6-yl)-4-(4-trifluoromethoxybenzyl)piperidin-4-ylamine;-   1-(7H-pyrolo[2,3-d]pyrimidin-4-yl)-4-(3-chlorobenzyl)piperidin-4-ylamine;-   4-(4-chlorobenzyl)-1-(1H-pyrrolo[2,3-b]pyridin-4-yl)-piperidin-4-ylamine;-   4-(2-chlorobenzyl)-1-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)piperidin-4-ylamine;-   4-(4-tert-Butylbenzyl)-1-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)piperidin-4-ylamine;-   4-(3-methoxybenzyl)-1-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)piperidin-4-ylamine;-   4-(3-trifluoromethoxybenzyl)-1-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)piperidin-4-ylamine;-   4-(2,4-dichlorobenzyl)-1-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)piperidin-4-ylamine;-   4-(2-chloro-4-fluorobenzyl)-1-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)piperidin-4-ylamine;-   4-(2,6-dichlorobenzyl)-1-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)piperidin-4-ylamine;-   [4-(4-chlorobenzyl)-1-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)piperidin-4-yl]methylamine;-   1-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-4-(2-trifluoromethoxybenzyl)piperidin-4-ylamine;-   4-(2,5-dichlorobenzyl)-1-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)piperidin-4-ylamine;-   4-(2,3-dichlorobenzyl)-1-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)piperidin-4-ylamine;-   4-(4-tert-butylbenzyl)-1-(1H-pyrrolo[2,3-b]pyridin-4-yl)-piperidin-4-ylamine;-   4-(2,4-dichlorobenzyl)-1-(1H-pyrrolo[2,3-b]pyridin-4-yl)-piperidin-4-ylamine;-   C-[4-(4-chlorophenyl)-1-(1H-pyrrolo[2,3-b]pyridin-4-yl)-piperidin-4-yl]-methylamine;-   4-amino-1-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-piperidine-4-carboxylic    acid 4-chloro-benzylamide;-   4-amino-1-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-piperidine-4-carboxylic    acid 3-chloro-benzylamide;-   4-amino-1-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-piperidine-4-carboxylic    acid 4-trifluoromethyl-benzylamide;-   4-amino-1-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-piperidine-4-carboxylic    acid 4-fluoro-benzylamide;-   4-amino-1-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-piperidine-4-carboxylic    acid 2-chloro-benzylamide;-   4-amino-1-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-piperidine-4-carboxylic    acid 4-trifluoromethoxy-benzylamide;-   4-amino-1-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-piperidine-4-carboxylic    acid (4-chloro-benzyl)-methyl-amide;-   4-amino-1-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-piperidine-4-carboxylic    acid 4-tert-butyl-benzylamide;-   4-amino-1-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-piperidine-4-carboxylic    acid 2,4-dichloro-benzylamide;-   4-amino-1-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-piperidine-4-carboxylic    acid 3,4-dichloro-benzylamide; and-   4-(4-chloro-benzyloxymethyl)-1-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-piperidin-4-ylamine;-   [4-amino-1-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-piperidin-4-yl]-(3,4-dihydro-1H-isoquinolin-2-yl)-methanone;-   [4-amino-1-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-piperidin-4-yl]-(2-phenyl-pyrrolidin-1-yl)-methanone;-   4-(4-chlorobenzyl)-1-(1H-pyrazolo[3,4-b]pyridin-4-yl)-piperidin-4-ylamine;-   4-(4-tert-butyl-benzyl)-1-(1H-pyrazolo[3,4-b]pyridin-4-yl)-piperidin-4-ylamine;-   4-(4-tert-butyl-benzyl)-1-(1H-pyrrolo[2,3-b]pyridin-4-yl)-piperidin-4-ylamine;-   N-[4-amino-1-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-piperidin-4-ylmethyl]-4-chloro-benzamide;-   4-biphenyl-4-ylmethyl-1-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-piperidin-4-ylamine;-   4-biphenyl-2-ylmethyl-1-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-piperidin-4-ylamine;-   4-(2-methoxy-benzyl)-1-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-piperidin-4-ylamine;-   4-naphthalen-1-ylmethyl-1-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-piperidin-4-ylamine;-   4-amino-1-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-piperidine-4-carboxylic    acid 4-chloro-2-fluoro-benzylamide;-   4-amino-1-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-piperidine-4-carboxylic    acid (biphenyl-3-ylmethyl)-amide;-   4-biphenyl-3-ylmethyl-1-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-piperidin-4-ylamine;    and-   4-(6-chloro-biphenyl-3-ylmethyl)-1-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-piperidin-4-ylamine;    and    salts, solvates, tautomers and N-oxides thereof.    Salts, Solvates. Tautomers, Isomers, N-Oxides. Esters, Prodrugs and    Isotopes

Unless otherwise specified, a reference to a particular compound alsoincludes ionic, salt, solvate, and protected forms thereof, for example,as discussed below.

Many compounds of the formula (I) can exist in the form of salts, forexample acid addition salts or, in certain cases salts of organic andinorganic bases such as carboxylate, sulphonate and phosphate salts. Allsuch salts are within the scope of this invention, and references tocompounds of the formula (I) include the salt forms of the compounds. Asin the preceding sections of this application, all references to formula(I) should be taken to refer also to formulae (Ia), (Ib), (Ic), (Id),(Ie), (II), (IIa), (III), (IV), (V), (VI) and sub-groups thereof unlessthe context indicates otherwise.

Salt forms may be selected and prepared according to methods describedin Pharmaceutical Salts Properties, Selection, and Use, P. HeinrichStahl (Editor), Camille G. Wermuth (Editor), ISBN: 3-90639-026-8,Hardcover, 388 pages, August 2002.

Acid addition salts may be formed with a wide variety of acids, bothinorganic and organic. Examples of acid addition salts include saltsformed with an acid selected from the group consisting of acetic,2,2-dichloroacetic, adipic, alginic, ascorbic (e.g. L-ascorbic),L-aspartic, benzenesulphonic, benzoic, 4-acetamidobenzoic, butanoic, (+)camphoric, camphor-sulphonic, (+)-(1S)-camphor-10-sulphonic, capric,caproic, caprylic, cinnamic, citric, cyclamic, dodecylsulphuric,ethane-1,2-disulphonic, ethanesulphonic, 2-hydroxyethanesulphonic,formic, fumaric, galactaric, gentisic, glucoheptonic, D-gluconic,glucuronic (e.g. D-glucuronic), glutamic (e.g. L-glutamic),α-oxoglutaric, glycolic, hippuric, hydrobromic, hydrochloric, hydriodic,isethionic, lactic (e.g. (+)-L-lactic and (±)-DL-lactic), lactobionic,maleic, malic, (−)-L-malic, malonic, (±)-DL-mandelic, methanesulphonic,naphthalenesulphonic (e.g. naphthalene-2-sulphonic),naphthalene-1,5-disulphonic, 1-hydroxy-2-naphthoic, nicotinic, nitric,oleic, orotic, oxalic, palmitic, pamoic, phosphoric, propionic,L-pyroglutamic, salicylic, 4-amino-salicylic, sebacic, stearic,succinic, sulphuric, tannic, (+)-L-tartaric, thiocyanic,toluenesulphonic (e.g. p-toluenesulphonic), undecylenic and valericacids, as well as acylated amino acids and cation exchange resins.

For example, if the compound is anionic, or has a functional group whichmay be anionic (e.g., —COOH may be —COO⁻), then a salt may be formedwith a suitable cation. Examples of suitable inorganic cations include,but are not limited to, alkali metal ions such as Na⁺ and K⁺, alkalineearth cations such as Ca²⁺ and Mg²⁺, and other cations such as Al³⁺.Examples of suitable organic cations include, but are not limited to,ammonium ion (i.e., NH₄ ⁺) and substituted ammonium ions (e.g., NH₃R⁺,NH₂R₂ ⁺, NHR₃ ⁺, NR₄ ⁺). Examples of some suitable substituted ammoniumions are those derived from: ethylamine, diethylamine,dicyclohexylamine, triethylamine, butylamine, ethylenediamine,ethanolamine, diethanolamine, piperazine, benzylamine,phenylbenzylamine, choline, meglumine, and tromethamine, as well asamino acids, such as lysine and arginine. An example of a commonquaternary ammonium ion is N(CH₃)₄ ⁺.

Where the compounds of the formula (I) contain an amine function, thesemay form quaternary ammonium salts, for example by reaction with analkylating agent according to methods well known to the skilled person.Such quaternary ammonium compounds are within the scope of formula (I).

The salt forms of the compounds of the invention are typicallypharmaceutically acceptable salts, and examples of pharmaceuticallyacceptable salts are discussed in Berge et al., 1977, “PharmaceuticallyAcceptable Salts,” J. Pharm. Sci., Vol. 66, pp. 1-19. However, saltsthat are not pharmaceutically acceptable may also be prepared asintermediate forms which may then be converted into pharmaceuticallyacceptable salts. Such non-pharmaceutically acceptable salts forms,which may be useful, for example, in the purification or separation ofthe compounds of the invention, also form part of the invention.

Compounds of the formula (I) containing an amine function may also formN-oxides. A reference herein to a compound of the formula (I) thatcontains an amine function also includes the N-oxide.

Where a compound contains several amine functions, one or more than onenitrogen atom may be oxidised to form an N-oxide. Particular examples ofN-oxides are the N-oxides of a tertiary amine or a nitrogen atom of anitrogen-containing heterocycle.

N-Oxides can be formed by treatment of the corresponding amine with anoxidizing agent such as hydrogen peroxide or a per-acid (e.g. aperoxycarboxylic acid), see for example Advanced Organic Chemistry, byJerry March, 4^(th) Edition, Wiley Interscience, pages. Moreparticularly, N-oxides can be made by the procedure of L. W. Deady (Syn.Comm. 1977, 7, 509-514) in which the amine compound is reacted withm-chloroperoxybenzoic acid (MCPBA), for example, in an inert solventsuch as dichloromethane.

Compounds of the formula (I) may exist in a number of differentgeometric isomeric, and tautomeric forms and references to compounds ofthe formula (I) include all such forms. For the avoidance of doubt,where a compound can exist in one of several geometric isomeric ortautomeric forms and only one is specifically described or shown, allothers are nevertheless embraced by formula (I).

For example, when J¹-J² is N═CR⁶, the tautomeric forms A and B arepossible for the bicyclic group.

When J¹-J² is N═N, the tautomeric forms C and D are possible for thebicyclic group.

When J¹-J² is HN—CO, the tautomeric forms E, F and G are possible forthe bicyclic group.

All such tautomers are embraced by formula (I).

Other examples of tautomeric forms include keto-, enol-, andenolate-forms, as in, for example, the following tautomeric pairs:keto/enol (illustrated below), imine/enamine, amide/imino alcohol,amidine/amidine, nitroso/oxime, thioketone/enethiol, andnitro/aci-nitro.

Where compounds of the formula (I) contain one or more chiral centres,and can exist in the form of two or more optical isomers, references tocompounds of the formula (I) include all optical isomeric forms thereof(e.g. enantiomers, epimers and diastereoisomers), either as individualoptical isomers, or mixtures (e.g. racemic mixtures) or two or moreoptical isomers, unless the context requires otherwise.

The optical isomers may be characterised and identified by their opticalactivity (i.e. as + and − isomers, or d and l isomers) or they may becharacterised in terms of their absolute stereochemistry using the “Rand S” nomenclature developed by Cahn, Ingold and Prelog, see AdvancedOrganic Chemistry by Jerry March, 4^(th) Edition, John Wiley & Sons, NewYork, 1992, pages 109-114, and see also Cahn, Ingold & Prelog, Angew.Chem. Int. Ed. Engl., 1966, 5, 385-415.

Optical isomers can be separated by a number of techniques includingchiral chromatography (chromatography on a chiral support) and suchtechniques are well known to the person skilled in the art.

Where compounds of the formula (I) exist as two or more optical isomericforms, one enantiomer in a pair of enantiomers may exhibit advantagesover the other enantiomer, for example, in terms of biological activity.Thus, in certain circumstances, it may be desirable to use as atherapeutic agent only one of a pair of enantiomers, or only one of aplurality of diastereoisomers. Accordingly, the invention providescompositions containing a compound of the formula (I) having one or morechiral centres, wherein at least 55% (e.g. at least 60%, 65%, 70%, 75%,80%, 85%, 90% or 95%) of the compound of the formula (I) is present as asingle optical isomer (e.g. enantiomer or diastereoisomer). In onegeneral embodiment, 99% or more (e.g. substantially all) of the totalamount of the compound of the formula (I) may be present as a singleoptical isomer (e.g. enantiomer or diastereoisomer).

The compounds of the invention include compounds with one or moreisotopic substitutions, and a reference to a particular element includeswithin its scope all isotopes of the element. For example, a referenceto hydrogen includes within its scope ¹H, ²H(D), and ³H(T). Similarly,references to carbon and oxygen include within their scope respectively¹²C, ¹³C and ¹⁴C and ¹⁶O and ¹⁸O.

The isotopes may be radioactive or non-radioactive. In one embodiment ofthe invention, the compounds contain no radioactive isotopes. Suchcompounds are preferred for therapeutic use. In another embodiment,however, the compound may contain one or more radioisotopes. Compoundscontaining such radioisotopes may be useful in a diagnostic context.

Esters such as carboxylic acid esters and acyloxy esters of thecompounds of formula (I) bearing a carboxylic acid group or a hydroxylgroup are also embraced by Formula (I). In one embodiment of theinvention, formula (I) includes within its scope esters of compounds ofthe formula (I) bearing a carboxylic acid group or a hydroxyl group. Inanother embodiment of the invention, formula (I) does not include withinits scope esters of compounds of the formula (I) bearing a carboxylicacid group or a hydroxyl group. Examples of esters are compoundscontaining the group —C(═O)OR, wherein R is an ester substituent, forexample, a C₁₋₇ alkyl group, a C₃₋₂₀ heterocyclyl group, or a C₅₋₂₀ arylgroup, preferably a C₁₋₇ alkyl group. Particular examples of estergroups include, but are not limited to, —C(═O)OCH₃, —C(═O)OCH₂CH₃,—C(═O)OC(CH₃)₃, and —C(═O)OPh. Examples of acyloxy (reverse ester)groups are represented by —OC(═O)R, wherein R is an acyloxy substituent,for example, a C₁₋₇ alkyl group, a C₃₋₂₀ heterocyclyl group, or a C₅₋₂₀aryl group, preferably a C₁₋₇ alkyl group. Particular examples ofacyloxy groups include, but are not limited to, —OC(═O)CH₃ (acetoxy),—OC(═O)CH₂CH₃, —OC(═O)C(CH₃)₃, —OC(═O)Ph, and —OC(═O)CH₂Ph.

Also encompassed by formula (I) are any polymorphic forms of thecompounds, solvates (e.g. hydrates), complexes (e.g. inclusion complexesor clathrates with compounds such as cyclodextrins, or complexes withmetals) of the compounds, and pro-drugs of the compounds. By “prodrugs”is meant for example any compound that is converted in vivo into abiologically active compound of the formula (I).

For example, some prodrugs are esters of the active compound (e.g., aphysiologically acceptable metabolically labile ester). Duringmetabolism, the ester group (—C(═O)OR) is cleaved to yield the activedrug. Such esters may be formed by esterification, for example, of anyof the carboxylic acid groups (—C(═O)OH) in the parent compound, with,where appropriate, prior protection of any other reactive groups presentin the parent compound, followed by deprotection if required.

Examples of such metabolically labile esters include those of theformula —C(═O)OR wherein R is:

C₁₋₇alkyl(e.g., —Me, —Et, -nPr, -iPr, -nBu, -sBu, -iBu, -tBu);C₁₋₇-aminoalkyl(e.g., aminoethyl; 2-(N,N-diethylamino)ethyl; 2-(4-morpholino)ethyl);andacyloxy-C₁₋₇alkyl(e.g., acyloxymethyl;acyloxyethyl;pivaloyloxymethyl;acetoxymethyl;1-acetoxyethyl;1-(1-methoxy-1-methyl)ethyl-carbonxyloxyethyl;1-(benzoyloxy)ethyl; isopropoxy-carbonyloxymethyl;1-isopropoxy-carbonyloxyethyl; cyclohexyl-carbonyloxymethyl;1-cyclohexyl-carbonyloxyethyl;cyclohexyloxy-carbonyloxymethyl;1-cyclohexyloxy-carbonyloxyethyl;(4-tetrahydropyranyloxy) carbonyloxymethyl;1-(4-tetrahydropyranyloxy)carbonyloxyethyl;(4-tetrahydropyranyl)carbonyloxymethyl; and1-(4-tetrahydropyranyl)carbonyloxyethyl).

Also, some prodrugs are activated enzymatically to yield the activecompound, or a compound which, upon further chemical reaction, yieldsthe active compound (for example, as in Antibody-directed Enzyme ProdrugTherapy (ADEPT), Gene-directed Enzyme Prodrug Therapy (GDEPT),Polymer-directed Enzyme Prodrug Therapy (PDEPT), Ligand-directed EnzymeProdrug Therapy (LIDEPT), etc.). For example, the prodrug may be a sugarderivative or other glycoside conjugate, or may be an amino acid esterderivative.

Methods for the Preparation of Compounds of the Formula (I)

In this section, references to compounds of the formula (I) includeformulae (Ia), (Ib), (Ic), (Id), (II), (III), (IV), (V), (VI) and eachof the sub-groups thereof as defined herein unless the context requiresotherwise.

In a further aspect, the invention provides a process for thepreparation of a compound of the formula. (I) as defined herein.

Compounds of the formula (I) wherein E is an aryl or heteroaryl groupcan be prepared by reaction of a compound of the formula (X) with acompound of the formula (XI) where (X) and (XI) may be suitablyprotected and wherein T, J¹, J², Q¹, Q², G, E, and R¹ to R⁵ are ashereinbefore defined, one of the groups X and Y is chlorine, bromine oriodine or a trifluoromethanesulphonate (triflate) group, and the otherone of the groups X and Y is a boronate residue, for example a boronateester or boronic acid residue.

The reaction can be carried out under typical Suzuki Coupling conditionsin the presence of a palladium catalyst such astetrakis(triphenylphosphine)palladium and a base (e.g. a carbonate suchas potassium carbonate). The reaction may be carried out in a polarsolvent, for example an aqueous solvent such as aqueous ethanol, or anether such as dimethoxyethane, and the reaction mixture is typicallysubjected to heating, for example to a temperature of 80° C. or more,e.g. a temperature in excess of 100° C.

An illustrative synthetic route involving a Suzuki coupling step isshown in Scheme 1. In Scheme 1, the bromo compound (XII) in which E isan aryl or heteroaryl group, is converted to a boronic acid (XIII) byreaction with an alkyl lithium such as butyl lithium and a borate ester(iPrO)₃B. The reaction is typically carried out in a dry polar solventsuch as tetrahydrofuran at a reduced temperature (for example −78° C.).

The resulting boronic acid (XIII) is then reacted with the N-protectedchloro compound (XIV) in the presence ofbis(triphenylphosphine)palladium under the conditions described above.The protecting group PG (which can be for example a tetrahydropyranyl(THP) group) is then removed by treatment with an acid such ashydrochloric acid to give the compound of the formula (I′).

In Scheme 1, where G is other than hydrogen, it is typically protectedwith a suitable protecting group of which examples are set out below.One particular protecting group which may be used in the context of aSuzuki coupling for protecting an amino group is the tert-butoxycarbonylgroup which can be introduced by reacting the amino group withdi-tert-butylcarbonate in the presence of a base such as triethylamine.Removal of the protecting group is typically accomplished at the sametime as removal of the protecting group PG on the bicyclic group.

In the preparative procedure outlined above, the coupling of the aryl orheteroaryl group E to the bicyclic group is accomplished by reacting ahalo-purine (or deaza analogue thereof) or halo-aryl or heteroarylcompound with a boronate ester or boronic acid in the presence of apalladium catalyst and base. Many boronates suitable for use inpreparing compounds of the invention are commercially available, forexample from Boron Molecular Limited of Noble Park, Australia, or fromCombi-Blocks Inc, of San Diego, USA. Where the boronates are notcommercially available, they can be prepared by methods known in theart, for example as described in the review article by N. Miyaura and A.Suzuki, Chem. Rev. 1995, 95, 2457. Thus, boronates can be prepared byreacting the corresponding bromo-compound with an alkyl lithium such asbutyl lithium and then reacting with a borate ester. The resultingboronate ester derivative can, if desired, be hydrolysed to give thecorresponding boronic acid.

Compounds of the formula (I) wherein E is a non-aromatic cyclic groupand is linked to the bicyclic group by a nitrogen atom can be preparedby the reaction of a compound of the formula (XVI) where T is N, with acompound of the formula (XVII) or a protected derivative thereof, whereR¹, Q¹, Q² and G are as defined herein and the ring E represents acyclic group E containing a nucleophilic NH group as a ring member.

The reaction is typically carried out in a polar solvent such as analcohol (e.g. ethanol, propanol or n-butanol) at an elevatedtemperature, for example a temperature in the region from 90° C. to 160°C., optionally in the presence of a non-interfering amine such astriethylamine. The reaction may be carried out in a sealed tube,particularly where the desired reaction temperature exceeds the boilingpoint of the solvent. When T is N, the reaction is typically carried outat a temperature in the range from about 100° C. to 130° C. but, when Tis CH, higher temperatures may be required, for example up to about 160°C., and hence higher boiling solvents such as dimethylformamide may beused. In general, an excess of the nucleophilic amine will be usedand/or an additional non-reacting base such as triethylamine will beincluded in the reaction mixture. Heating of the reaction mixture may beaccomplished by normal means or by the use of a microwave heater.

In order to prepare compounds of the formula (I) wherein T is CH, thehydrogen atom of the group CH may be replaced by an activating group inorder to facilitate nucleophilic displacement of the chlorine atom bythe amine (XVII). The activating group is typically one which can beremoved subsequent to the nucleophilic displacement reaction. One suchactivating group is an ester group such as ethoxycarbonyl ormethoxycarbonyl which can be removed by hydrolysis and decarboxylation.Hydrolysis of the ethoxycarbonyl or methoxycarbonyl group to thecarboxylic acid is typically carried out using an aqueous alkali such assodium hydroxide, and the decarboxylation step is typically conducted byheating to an elevated temperature (e.g. 150° C. to 190° C.).

Compounds of the formula (XVI) are commercially available or can beprepared according to methods well known to the skilled person. Forexample, compounds of the formula (XVI) where T is N and J¹-J² is CH═Ncan be prepared from the corresponding hydroxy compound by reaction witha chlorinating agent such as POCl₃. Compounds of the formula (XVI) whereJ¹-J² is HN—C(O) can be prepared by the reaction of an ortho-diaminocompound of the formula (XVIII) with carbonyl di-imidazole in thepresence of a non-interfering base such as triethylamine.

Compounds of the formula (XVI) where T is CR⁵ and J¹-J² is (R⁷)H═CH(R⁶)can be prepared from the corresponding N-oxide of the formula (XIX) byreaction with phosphorus oxychloride at an elevated temperature, forexample the reflux temperature of POCl₃.

Intermediate compounds of the formula (XVII) wherein E is a piperidinegroup, Q¹ is a saturated hydrocarbon linking group and Q¹ and Q² areboth linked to the 4-position of the piperidine group can be prepared bythe sequence of reactions shown in Scheme 2.

In Scheme 2, 4-methoxycarbonyl-piperidine is first protected in standardfashion, for example by means of a t-butyloxycarbonyl (boc) group byreaction with di-tert-butylcarbonate in the presence of anon-interfering base to give the protected compound (XX). The protectedpiperidine carboxymethyl ester (XX) is then alkylated at the α-positionrelative to the carbonyl group of the ester by reacting with a strongbase such as lithium diisopropylamide (LDA) and a compound of theformula R¹Q¹-Hal where Hal is a halogen, preferably bromine, and Q¹ is asaturated hydrocarbon group. The ester (XXI) is then hydrolysed to thecorresponding carboxylic acid (XXII) using an alkali metal hydroxidesuch as sodium hydroxide. The carboxylic acid (XXII) can be used toprepare a range of different amine intermediates which can, in turn, beconverted into compounds of the formula (II). For example, as shown inScheme 2, the carboxylic acid can be converted to the acid chloride(e.g. by treatment with oxalyl chloride and optionally a catalyticquantity of DMF, or by treatment of a salt of the acid with oxalylchloride) and then reacted with sodium azide to form the acid azide (notshown). The acid azide can then be heated to bring about rearrangementin a Curtius reaction (see Advanced Organic Chemistry, 4^(th) edition,by Jerry March, John Wiley & sons, 1992, pages 1091-1092) to givecompound (XXIII) in which the amino group is attached directly to thepiperidine ring. The amine (XXIII) is then deprotected according tostandard methods (e.g. using hydrochloric acid in the case of a Bocprotecting group) and reacted with a compound of the formula (XIV) togive a compound of the formula (I).

In an alternative sequence of reactions, the ester (XXI) can be reducedto the corresponding alcohol which, following deprotection of thepiperidine ring nitrogen atom, can be reacted with a compound of theformula (XXI) to give a compound of the formula (I) in which Q² is CH₂and G is OH. Alternatively, the alcohol can be oxidised to the aldehydeusing Dess-Martin periodinane (see Dess, D. B.; Martin, J. C. J. Org.Soc., 1983, 48, 4155 and Organic Syntheses, Vol. 77, 141) ortetrapropylammonium perruthenate (TPAP). The resulting aldehyde can beused for a variety of synthetic interconversions such as reductiveamination using sodium cyanoborohydride and an amine HNR²R³ to give acompound of the formula (XVII) in which Q2 is CH₂ and G is HNR²R³.

The carboxylic acid (XXII) can also be converted to an amide by reactionwith an amine HNR²R³ under conditions suitable for forming an amidebond. The coupling reaction between the acid (XXII) and the amine HNR²R³is preferably carried out in the presence of a reagent of the typecommonly used in the formation of peptide linkages. Examples of suchreagents include 1,3-dicyclohexylcarbodiimide (DCC) (Sheehan et al, J.Amer. Chem. Soc. 1955, 77, 1067),1-ethyl-3-(3′-dimethylaminopropyl)-carbodiimide (referred to hereineither as EDC or EDAC) (Sheehan et al, J. Org. Chem., 1961, 26, 2525),uronium-based coupling agents such asO-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluroniumhexafluorophosphate (HATU) and phosphonium-based coupling agents such as1-benzo-triazolyloxytris-(pyrrolidino)phosphonium hexafluorophosphate(PyBOP) (Castro et al, Tetrahedron Letters, 1990, 31, 205).Carbodiimide-based coupling agents are advantageously used incombination with 1-hydroxy-7-azabenzotriazole (HOAt) (L. A. Carpino, J.Amer. Chem. Soc., 1993, 115, 4397) or 1-hydroxybenzotriazole (HOBt)(Konig et al, Chem. Ber., 103, 708, 2024-2034). Preferred couplingreagents include EDC (EDAC) and DCC in combination with HOAt or HOBt.

The coupling reaction is typically carried out in a non-aqueous,non-protic solvent such as acetonitrile, dioxan, dimethylsulphoxide,dichloromethane, dimethylformamide or N-methylpyrrolidine, or in anaqueous solvent optionally together with one or more miscibleco-solvents. The reaction can be carried out at room temperature or,where the reactants are less reactive (for example in the case ofelectron-poor anilines bearing electron withdrawing groups such assulphonamide groups) at an appropriately elevated temperature. Thereaction may be carried out in the presence of a non-interfering base,for example a tertiary amine such as triethylamine orN,N-diisopropylethylamine.

Where the amine HNR²R³ is ammonia, the amide coupling reaction can becarried out using 1,1′-carbonyldiimidazole (CDI) to activate thecarboxylic acid before addition of the ammonia.

As an alternative, a reactive derivative of the carboxylic acid, e.g. ananhydride or acid chloride, may be used. Reaction with a reactivederivative such an anhydride is typically accomplished by stirring theamine and anhydride at room temperature in the presence of a base suchas pyridine.

The resulting amide (not shown) can be reduced using a hydride reducingagent such as lithium aluminium hydride in the presence of aluminiumchloride to give the corresponding amine.

Compounds of the formula ((XVII) in which E is a piperidine group, Q¹ isa bond and R¹ is an aryl or heteroaryl group can be prepared using thesequence of steps shown in Scheme 3.

As shown in Scheme 3, the nitrile (XXV) in which R¹ is an aryl orheteroaryl group is reacted with a base and N-protected (PG=protectinggroup) bis-(2-chloroethyl)amine to give the piperidine nitrile (XXVI)which can then be reduced to give the amine (XXVII) using Raney nickeland then deprotected (e.g. using HCl when the protecting group is acidlabile) to give amine (XXVIII). Alternatively, the nitrile (XXVI) can bereacted with a compound of the formula (XVI) to give a compound of theformula (I) in which Q² and G together form a nitrile group.

Compounds of the formula (I) in which E is a piperidine ring, Q² is abond and G is an amino group can also be prepared by the reactionsequence shown in Scheme 4.

As shown in Scheme 4, a protected 4-piperidone (XXIX), in which PG is aprotecting group such as Boc, is reacted with tert-butylsulphinimide inthe presence of titanium tetraethoxide in a dry polar solvent such asTHF to give the sulphinimine (XXX). The reaction is typically carriedout with heating, for example to the reflux temperature of the solvent.The sulphinimine (XXX) is then reacted with an organometallic reagent,for example a Grignard reagent such as an aralkyl or arylmagnesiumbromide, suitable for introducing the moiety R¹-Q¹, to give thesulphinamide (XXXI). The tert-butylsulphinyl group can then be removedby hydrolysis in a hydrochloric acid/dioxane/methanol mixture to givethe amine (XXIV). The amine (XXIV) can then be reacted with achloro-heterocycle (XVI) under the conditions described above to givethe product (XXXI), i.e. a compound of the formula (I) in which E ispiperidine, Q² is a bond and G is an amino group.

The corresponding compound wherein Q² is a bond and G is an alkylamino(e.g. methylamino) group can be prepared from the tert-butylsulphinylintermediate compound (XXXI) by reaction of the intermediate (XXXI) witha strong base, e.g. a metal hydride such as sodium hydride, followed bythe addition of an alkyl halide such as methyl iodide. The reaction istypically carried out in a polar aprotic solvent such asdimethylformamide at a reduced temperature, for example 0-5° C.

Compounds of the formula (I) where Q¹ contains an amide bond can beprepared from intermediates of the formulae (XXXII) and (XXXIII) byreaction with intermediate (XI) above using a Suzuki coupling procedure(when X^(L) is bromine) or by reaction with intermediate (XVI) (whenX^(L) is hydrogen and the group E contains a nucleophilic nitrogen atom)using the methods and conditions described above.

In formulae (XXXII) and (XXXIII), Q^(1a) and Q^(1b) are each a bond or aresidue of the group Q¹, and X^(L) is hydrogen or halogen such asbromine. For example, Q^(1a) can be a bond and Q^(1b) can be a group CH₂and vice versa.

The compounds of formulae (XXXII) and (XXXIII) can be prepared byreacting together the appropriate carboxylic acid or activatedderivative thereof (e.g. acid chloride) and the appropriate amine usingthe amide-forming conditions described above.

The formation of compounds of the formula (I) wherein the moiety Q¹contains an amide group is illustrated by the sequence of reactions setout in Scheme 5.

In Scheme 5, the boc-protected piperidine amino acid (XXXIV) is reactedwith the arylamine or heteroarylamine R¹-NH₂ using the amide formingconditions set out above. Thus, for example, the amide-forming reactioncan be carried out using HATU (see above) in the presence of a base suchas N-ethyldiisopropylamine in a polar solvent such as DMF. The amide(XXXV) is then deprotected; in this case by treatment with acid toremove the boc group; and then reacted with the bicyclic chloro compound(XVI) at elevated temperature (e.g. approximately 100° C.) to give theproduct (XXXVII). The reaction with the chloro compound is typicallycarried out in a polar solvent such as a high boiling alcohol (e.g.n-butanol) in the presence of a non-interfering base such astriethylamine.

Compounds of the formula (I) in which Q¹ contains an ether linkage canbe prepared in a manner analogous to the methods described above for thecompounds in which Q¹ contains an amide bond. The preparation ofcompounds containing an ether linkage is illustrated by the sequence ofreactions set out in Scheme 6.

In Scheme 6, the N-protected piperidine amino acid (XXXIV) is reduced tothe corresponding alcohol (XXXVIII) using a reducing agent such aslithium aluminium hydride in a polar aprotic solvent such astetrahydrofuran, typically at around room temperature. The alcohol(XXXVIII) is then treated with a strong base, e.g. a metal hydride suchas sodium hydride to form the alcholate which is then reacted with thearylmethyl- or heteroarylmethyl bromide R¹-CH₂—Br to form the ether(XXXIX). The ether-forming reaction is typically carried out at areduced temperature (e.g. approximately 0° C. using an aprotic polarsolvent such as DMF. The ether is then deprotected by standard methodsand the deprotected ether (XL) is reacted with the chloro-compound (XVI)under the conditions described above to give the product (XLI).

Compounds of the formula (I) wherein T is CH, E is a piperidine groupand J¹-J² is CH═N or CH═CH can be prepared according to the procedureillustrated in Scheme 7.

In the sequence of reactions shown in Scheme 7, the starting material isthe chlorinated carboxy ester compound (XLIII) which can be prepared bymethods generally analogous to methods described in J. Heterocycl. Chem.1972, 235 and Bioorg. Med. Chem. Lett. 2003, 2405 followed by removal ofany unwanted protecting groups where necessary. In formula (XLIII), AlkOis an alkoxy group, e.g. a C₁₋₃ alkoxy group such as methoxy or ethoxy(particularly ethoxy).

The substituted piperidine compound (XLII), suitably protected wherenecessary, is reacted with the chlorinated carboxy ester compound(XLIII), to give an ester intermediate of the formula (XLIV). Thereaction may be carried out in a polar solvent such as a higher boilingalcohol (e.g. n-butanol) in the presence of a non-interfering base suchas triethylamine at an elevated temperature (e.g. 90° C. to 130° C.,more typically 100° C. to 120° C.). Heating can be effected by means ofa microwave heater.

The carboxy ester group in the chlorinated carboxy ester compound(XLIII) functions as an activating group, rendering the chlorine atommore susceptible to nucleophilic displacement. Once the nucleophilicdisplacement reaction has taken place, the carboxy ester group hasserved its purpose and can be removed. Accordingly, hydrolysis of theester intermediate (XLIV) to the carboxylic acid (XLV) is carried outusing an aqueous alkali metal hydroxide such as potassium hydroxide orsodium hydroxide with heating where necessary. The carboxylic acid (XLV)is then decarboxylated to give the product (XLVI) by heating to anelevated temperature in excess of 100° C., for example a temperature inthe range from about 120° C. to about 180° C.).

Once formed, many compounds of the formula (I) can be converted intoother compounds of the formula (I) using standard functional groupinterconversions.

For example, compounds of the formula (I) or protected forms thereofwherein J¹-J² is CH═N can be converted into the corresponding compoundwhere J¹-J² is N—C(CO) by bromination at the carbon atom in J¹-J² with abrominating agent such as N-bromosuccinimide (NBS) followed byhydrolysis with a mineral acid such as hydrochloric acid.

Other examples of interconversions include the reduction of compounds ofthe formula (I) in which the NR²R³ forms part of a nitrile group to thecorresponding amine. Compounds in which NR²R³ is an NH₂ group can beconverted to the corresponding alkylamine by reductive alkylation, or byformation of the N-Boc derivative and reaction with an alkylating agentsuch as methyl iodide in the presence of a base. Alternatively, theamine can be converted to a cyclic group by methods well known to theskilled person.

Examples of functional group interconversions and reagents andconditions for carrying out such conversions can be found in, forexample, Advanced Organic Chemistry, by Jerry March, 4^(th) edition,119, Wiley Interscience, New York, Fiesers' Reagents for OrganicSynthesis, Volumes 1-17, John Wiley, edited by Mary Fieser (ISBN:0-471-58283-2), and Organic Syntheses, Volumes 1-8, John Wiley, editedby Jeremiah P. Freeman (ISBN: 0471-31192-8).

Protecting Groups

In many of the reactions described above, it may be necessary to protectone or more groups to prevent reaction from taking place at anundesirable location on the molecule. Examples of protecting groups, andmethods of protecting and deprotecting functional groups, can be foundin Protective Groups in Organic Synthesis (T. Green and P. Wuts; 3rdEdition; John Wiley and Sons, 1999).

A hydroxy group may be protected, for example, as an ether (—OR) or anester (—OC(═O)R), for example, as: a t-butyl ether; a benzyl, benzhydryl(diphenylmethyl), or trityl (triphenylmethyl)ether; a trimethylsilyl ort-butyldimethylsilyl ether; or an acetyl ester (—OC(═O)CH₃, —OAc). Analdehyde or ketone group may be protected, for example, as an acetal(R—CH(OR)₂) or ketal (R₂C(OR)₂), respectively, in which the carbonylgroup (>C═O) is converted to a diether (>C(OR)₂), by reaction with, forexample, a primary alcohol. The aldehyde or ketone group is readilyregenerated by hydrolysis using a large excess of water in the presenceof acid. An amine group may be protected, for example, as an amide(—NRCO—R) or a urethane (—NRCO—OR), for example, as: a methyl amide(—NHCO—CH₃); a benzyloxy amide (—NHCO—OCH₂C₆H₅, —NH-Cbz); as a t-butoxyamide (—NHCO—OC(CH₃)₃, —NH-Boc); a 2-biphenyl-2-propoxy amide(—NHCO—OC(CH₃)₂C₆H₄C₆H₅, —NH-Bpoc), as a 9-fluorenylmethoxy amide(—NH-Fmoc), as a 6-nitroveratryloxy amide (—NH-Nvoc), as a2-trimethylsilylethyloxy amide (—NH-Teoc), as a 2,2,2-trichloroethyloxyamide (—NH-Troc), as an allyloxy amide (—NH-Alloc), or as a2-(phenylsulphonyl)ethyloxy amide (—NH-Psec). Other protecting groupsfor amines, such as cyclic amines and heterocyclic N—H groups, includetoluenesulphonyl (tosyl) and methanesulphonyl (mesyl) groups and benzylgroups such as a para-methoxybenzyl (PMB) group. A carboxylic acid groupmay be protected as an ester for example, as: an C₁₋₇ alkyl ester (e.g.,a methyl ester; a t-butyl ester); a C₁₋₇ haloalkyl ester (e.g., a C₁₋₇trihaloalkyl ester); a triC₁₋₇ alkylsilyl-C₁₋₇alkyl ester; or a C₅₋₂₀aryl-C₁₋₇ alkyl ester (e.g., a benzyl ester; a nitrobenzyl ester); or asan amide, for example, as a methyl amide. A thiol group may beprotected, for example, as a thioether (—SR), for example, as: a benzylthioether; an acetamidomethyl ether (—S—CH₂NHC(═O)CH₃).

Isolation and Purification of the Compounds of the Invention

The compounds of the invention can be isolated and purified according tostandard techniques well known to the person skilled in the art. Onetechnique of particular usefulness in purifying the compounds ispreparative liquid chromatography using mass spectrometry as a means ofdetecting the purified compounds emerging from the chromatographycolumn.

Preparative LC-MS is a standard and effective method used for thepurification of small organic molecules such as the compounds describedherein. The methods for the liquid chromatography (LC) and massspectrometry (MS) can be varied to provide better separation of thecrude materials and improved detection of the samples by MS.Optimisation of the preparative gradient LC method will involve varyingcolumns, volatile eluents and modifiers, and gradients. Methods are wellknown in the art for optimising preparative LC-MS methods and then usingthem to purify compounds. Such methods are described in Rosentreter U,Huber U.; Optimal fraction collecting in preparative LC/MS; J CombChem.; 2004; 6(2), 159-64 and Leister W, Strauss K, Wisnoski D, Zhao Z,Lindsley C., Development of a custom high-throughput preparative liquidchromatography/mass spectrometer platform for the preparativepurification and analytical analysis of compound libraries; J CombChem.; 2003; 5(3); 322-9.

Chemical Intermediates

Many of the chemical intermediates described above are novel per se andsuch novel intermediates form a further aspect of the invention.

Examples of such intermediates include, but are not limited to,protected forms of compounds of the formula (I) and sub-groups thereof,such as protected forms of compounds of the formulae (I′), (XXXI),(XXXVII), (XLI) and (XLVI), as well as compounds of the formulae (XLIV)and (XLV) and protected forms thereof.

Particular examples of compounds of the formula (XLIV) and protectedforms thereof include:

-   4-[4-(4-chlorophenyl)-4-(1,3-dioxo-1,3-dihydroisoindol-2-ylmethyl)-piperidin-1-yl]-1H-pyrrolo[2,3-b]pyridine-5-carboxylic    acid ethyl-ester;-   4-[4-amino-4-(4-chlorobenzyl)-piperidin-1-yl]-1H-pyrazolo[3,4-b]pyridine-5-carboxylic    acid ethyl ester; and-   4-[4-amino-4-(4-tert-butyl-benzyl)-piperidin-1-yl]-1H-pyrazolo[3,4-b]pyridine-5-carboxylic    acid ethyl ester.

Particular examples of compounds of the formula (XLV) and protectedforms thereof include:

-   4-[4-(4-chlorophenyl)-4-(1,3-dioxo-1,3-dihydroisoindol-2-ylmethyl)-piperidin-1-yl]-1H-pyrrolo[2,3-b]pyridine-5-carboxylic    acid;-   4-[4-amino-4-(4-chlorobenzyl)-piperidin-1-yl]-1H-pyrazolo[3,4-b]pyridine-5-carboxylic    acid; and-   4-[4-amino-4-(4-tert-butyl-benzyl)-piperidin-1-yl]-1H-pyrazolo[3,4-b]pyridine-5-carboxylic    acid.

Pharmaceutical Formulations

While it is possible for the active compound to be administered alone,it is preferable to present it as a pharmaceutical composition (e.g.formulation) comprising at least one active compound of the inventiontogether with one or more pharmaceutically acceptable carriers,adjuvants, excipients, diluents, fillers, buffers, stabilisers,preservatives, lubricants, or other materials well known to thoseskilled in the art and optionally other therapeutic or prophylacticagents.

Thus, the present invention further provides pharmaceuticalcompositions, as defined above, and methods of making a pharmaceuticalcomposition comprising admixing at least one active compound, as definedabove, together with one or more pharmaceutically acceptable carriers,excipients, buffers, adjuvants, stabilizers, or other materials, asdescribed herein.

The term “pharmaceutically acceptable” as used herein pertains tocompounds, materials, compositions, and/or dosage forms which are,within the scope of sound medical judgment, suitable for use in contactwith the tissues of a subject (e.g. human) without excessive toxicity,irritation, allergic response, or other problem or complication,commensurate with a reasonable benefit/risk ratio. Each carrier,excipient, etc. must also be “acceptable” in the sense of beingcompatible with the other ingredients of the formulation.

Accordingly, in a further aspect, the invention provides compounds ofthe formula (I) and sub-groups thereof as defined herein in the form ofpharmaceutical compositions.

The pharmaceutical compositions can be in any form suitable for oral,parenteral, topical, intranasal, ophthalmic, otic, rectal,intra-vaginal, or transdermal administration. Where the compositions areintended for parenteral administration, they can be formulated forintravenous, intramuscular, intraperitoneal, subcutaneous administrationor for direct delivery into a target organ or tissue by injection,infusion or other means of delivery.

Pharmaceutical formulations adapted for parenteral administrationinclude aqueous and non-aqueous sterile injection solutions which maycontain anti-oxidants, buffers, bacteriostats and solutes which renderthe formulation isotonic with the blood of the intended recipient; andaqueous and non-aqueous sterile suspensions which may include suspendingagents and thickening agents. The formulations may be presented inunit-dose or multi-dose containers, for example sealed ampoules andvials, and may be stored in a freeze-dried (lyophilized) conditionrequiring only the addition of the sterile liquid carrier, for examplewater for injections, immediately prior to use.

Extemporaneous injection solutions and suspensions may be prepared fromsterile powders, granules and tablets.

In one preferred embodiment of the invention, the pharmaceuticalcomposition is in a form suitable for i.v. administration, for exampleby injection or infusion.

In another preferred embodiment, the pharmaceutical composition is in aform suitable for sub-cutaneous (s.c.) administration.

Pharmaceutical dosage forms suitable for oral administration includetablets, capsules, caplets, pills, lozenges, syrups, solutions, powders,granules, elixirs and suspensions, sublingual tablets, wafers or patchesand buccal patches.

Pharmaceutical compositions containing compounds of the formula (I) canbe formulated in accordance with known techniques, see for example,Remington's Pharmaceutical Sciences, Mack Publishing Company, Easton,Pa., USA.

Thus, tablet compositions can contain a unit dosage of active compoundtogether with an inert diluent or carrier such as a sugar or sugaralcohol, e.g. lactose, sucrose, sorbitol or mannitol; and/or a non-sugarderived diluent such as sodium carbonate, calcium phosphate, calciumcarbonate, or a cellulose or derivative thereof such as methylcellulose, ethyl cellulose, hydroxypropyl methyl cellulose, and starchessuch as corn starch. Tablets may also contain such standard ingredientsas binding and granulating agents such as polyvinylpyrrolidone,disintegrants (e.g. swellable crosslinked polymers such as crosslinkedcarboxymethylcellulose), lubricating agents (e.g. stearates),preservatives (e.g. parabens), antioxidants (e.g. BHT), buffering agents(for example phosphate or citrate buffers), and effervescent agents suchas citrate/bicarbonate mixtures. Such excipients are well known and donot need to be discussed in detail here.

Capsule formulations may be of the hard gelatin or soft gelatin varietyand can contain the active component in solid, semi-solid, or liquidform. Gelatin capsules can be formed from animal gelatin or synthetic orplant derived equivalents thereof.

The solid dosage forms (e.g. tablets, capsules etc.) can be coated orun-coated, but typically have a coating, for example a protective filmcoating (e.g. a wax or varnish) or a release controlling coating. Thecoating (e.g. a Eudragit™ type polymer) can be designed to release theactive component at a desired location within the gastro-intestinaltract. Thus, the coating can be selected so as to degrade under certainpH conditions within the gastrointestinal tract, thereby selectivelyrelease the compound in the stomach or in the ileum or duodenum.

Instead of, or in addition to, a coating, the drug can be presented in asolid matrix comprising a release controlling agent, for example arelease delaying agent which may be adapted to selectively release thecompound under conditions of varying acidity or alkalinity in thegastrointestinal tract. Alternatively, the matrix material or releaseretarding coating can take the form of an erodible polymer (e.g. amaleic anhydride polymer) which is substantially continuously eroded asthe dosage form passes through the gastrointestinal tract. As a furtheralternative, the active compound can be formulated in a delivery systemthat provides osmotic control of the release of the compound. Osmoticrelease and other delayed release or sustained release formulations maybe prepared in accordance with methods well known to those skilled inthe art.

Compositions for topical use include ointments, creams, sprays, patches,gels, liquid drops and inserts (for example intraocular inserts). Suchcompositions can be formulated in accordance with known methods.

Compositions for parenteral administration are typically presented assterile aqueous or oily solutions or fine suspensions, or may beprovided in finely divided sterile powder form for making upextemporaneously with sterile water for injection.

Examples of formulations for rectal or intra-vaginal administrationinclude pessaries and suppositories which may be, for example, formedfrom a shaped moldable or waxy material containing the active compound.

Compositions for administration by inhalation may take the form ofinhalable powder compositions or liquid or powder sprays, and can beadministrated in standard form using powder inhaler devices or aerosoldispensing devices. Such devices are well known. For administration byinhalation, the powdered formulations typically comprise the activecompound together with an inert solid powdered diluent such as lactose.

The compounds of the inventions will generally be presented in unitdosage form and, as such, will typically contain sufficient compound toprovide a desired level of biological activity. For example, aformulation intended for oral administration may contain from 0.1milligrams to 2 grams of active ingredient, more usually from 10milligrams to 1 gram, for example, 50 milligrams to 500 milligrams.

The active compound will be administered to a patient in need thereof(for example a human or animal patient) in an amount sufficient toachieve the desired therapeutic effect.

Protein Kinase Inhibitory Activity

The activity of the compounds of the invention as inhibitors of proteinkinase A and protein kinase B can be measured using the assays set forthin the examples below and the level of activity exhibited by a givencompound can be defined in terms of the IC50 value. Preferred compoundsof the present invention are compounds having an IC₅₀ value of less than1 μM, more preferably less than 0.1 μM, against protein kinase B.

Some of the compounds of the formula (I) are selective inhibitors of PKBrelative to PKA, i.e. the IC₅₀ values against PKB are from 5 to 10 timeslower, and more preferably greater than 10 times lower, than the IC₅₀values against PKA.

Therapeutic Uses Prevention or Treatment of Proliferative Disorders

The compounds of the formula (I) are inhibitors of protein kinase A andprotein kinase B. As such, they are expected to be useful in providing ameans of preventing the growth of or inducing apoptosis of neoplasias.It is therefore anticipated that the compounds will prove useful intreating or preventing proliferative disorders such as cancers. Inparticular tumours with deletions or inactivating mutations in PTEN orloss of PTEN expression or rearrangements in the (T-cell lytmphocyte)TCL-1 gene may be particularly sensitive to PKB inhibitors. Tumourswhich have other abnormalities leading to an upregulated PKB pathwaysignal may also be particularly sensitive to inhibitors of PKB. Examplesof such abnormalities include but are not limited to overexpression ofone or more PI3K subunits, over-expression of one or more PKB isoforms,or mutations in PI3K, PDK1, or PKB which lead to an increase in thebasal activity of the enzyme in question, or upregulation oroverexpression or mutational activation of a growth factor receptor suchas a growth factor selected from the epidermal growth factor receptor(EGFR), fibroblast growth factor receptor (FGFR), platelet derivedgrowth factor receptor (PDGFR), insulin-like growth factor 1 receptor(IGF-1R) and vascular endothelial growth factor receptor (VEGFR)families.

It is also envisaged that the compounds of the invention will be usefulin treating other conditions which result from disorders inproliferation or survival such as viral infections, andneurodegenerative diseases for example. PKB plays an important role inmaintaining the survival of immune cells during an immune response andtherefore PKB inhibitors could be particularly beneficial in immunedisorders including autoimmune conditions.

Therefore, PKB inhibitors could be useful in the treatment of diseasesin which there is a disorder of proliferation, apoptosis ordifferentiation.

PKB inhibitors may also be useful in diseases resulting from insulinresistance and insensitivity, and the disruption of glucose, energy andfat storage such as metabolic disease and obesity.

Examples of cancers which may be inhibited include, but are not limitedto, a carcinoma, for example a carcinoma of the bladder, breast, colon(e.g. colorectal carcinomas such as colon adenocarcinoma and colonadenoma), kidney, epidermal, liver, lung, for example adenocarcinoma,small cell lung cancer and non-small cell lung carcinomas, esophagus,gall bladder, ovary, pancreas e.g. exocrine pancreatic carcinoma,stomach, cervix, endometrium, thyroid, prostate, or skin, for examplesquamous cell carcinoma; a hematopoietic tumour of lymphoid lineage, forexample leukaemia, acute lymphocytic leukaemia, B-cell lymphoma, T-celllymphoma, Hodgkin's lymphoma, non-Hodgkin's lymphoma, hairy celllymphoma, or Burkett's lymphoma; a hematopoietic tumour of myeloidlineage, for example acute and chronic myelogenous leukaemias,myelodysplastic syndrome, or promyelocytic leukaemia; thyroid follicularcancer; a tumour of mesenchymal origin, for example fibrosarcoma orhabdomyosarcoma; a tumour of the central or peripheral nervous system,for example astrocytoma, neuroblastoma, glioma or schwannoma; melanoma;seminoma; teratocarcinoma; osteosarcoma; xenoderoma pigmentosum;keratoctanthoma; thyroid follicular cancer; or Kaposi's sarcoma.

Thus, in the pharmaceutical compositions, uses or methods of thisinvention for treating a disease or condition comprising abnormal cellgrowth, the disease or condition comprising abnormal cell growth in oneembodiment is a cancer.

Particular subsets of cancers include breast cancer, ovarian cancer,colon cancer, prostate cancer, oesophageal cancer, squamous cancer andnon-small cell lung carcinomas.

A further subset of cancers includes breast cancer, ovarian cancer,prostate cancer, endometrial cancer and glioma.

It is also possible that some protein kinase B inhibitors can be used incombination with other anticancer agents. For example, it may bebeneficial to combine of an inhibitor that induces apoptosis withanother agent which acts via a different mechanism to regulate cellgrowth thus treating two of the characteristic features of cancerdevelopment. Examples of such combinations are set out below.

Immune Disorders

Immune disorders for which PKA and PKB inhibitors may be beneficialinclude but are not limited to autoimmune conditions and chronicinflammatory diseases, for example systemic lupus erythematosus,autoimmune mediated glomerulonephritis, rheumatoid arthritis, psoriasis,inflammatory bowel disease, and autoimmune diabetes mellitus, Eczemahypersensitivity reactions, asthma, COPD, rhinitis, and upperrespiratory tract disease.

Other Therapeutic Uses

PKB plays a role in apoptosis, proliferation, differentiation andtherefore PKB inhibitors could also be useful in the treatment of thefollowing diseases other than cancer and those associated with immunedysfunction; viral infections, for example herpes virus, pox virus,Epstein-Barr virus, Sindbis virus, adenovirus, HIV, HPV, HCV and HCMV;prevention of AIDS development in HIV-infected individuals;cardiovascular diseases for example cardiac hypertrophy, restenosis,atherosclerosis; neurodegenerative disorders, for example Alzheimer'sdisease, AIDS-related dementia, Parkinson's disease, amyotropic lateralsclerosis, retinitis pigmentosa, spinal muscular atropy and cerebellardegeneration; glomerulonephritis; myelodysplastic syndromes, ischemicinjury associated myocardial infarctions, stroke and reperfusion injury,degenerative diseases of the musculoskeletal system, for example,osteoporosis and arthritis, aspirin-sensitive rhinosinusitis, cysticfibrosis, multiple sclerosis, kidney diseases.

Methods of Treatment

It is envisaged that the compounds of the formula (I) will useful in theprophylaxis or treatment of a range of disease states or conditionsmediated by protein kinase A and/or protein kinase B. Examples of suchdisease states and conditions are set out above.

Compounds of the formula (I) are generally administered to a subject inneed of such administration, for example a human or animal patient,preferably a human.

The compounds will typically be administered in amounts that aretherapeutically or prophylactically useful and which generally arenon-toxic. However, in certain situations (for example in the case oflife threatening diseases), the benefits of administering a compound ofthe formula (I) may outweigh the disadvantages of any toxic effects orside effects, in which case it may be considered desirable to administercompounds in amounts that are associated with a degree of toxicity.

The compounds may be administered over a prolonged term to maintainbeneficial therapeutic effects or may be administered for a short periodonly. Alternatively they may be administered in a pulsatile manner.

A typical daily dose of the compound can be in the range from 100picograms to 100 milligrams per kilogram of body weight, more typically10 nanograms to 10 milligrams per kilogram of bodyweight although higheror lower doses may be administered where required. Ultimately, thequantity of compound administered will be commensurate with the natureof the disease or physiological condition being treated and will be atthe discretion of the physician.

The compounds of the formula (I) can be administered as the soletherapeutic agent or they can be administered in combination therapywith one of more other compounds for treatment of a particular diseasestate, for example a neoplastic disease such as a cancer as hereinbeforedefined. Examples of other therapeutic agents or treatments that may beadministered together (whether concurrently or at different timeintervals) with the compounds of the formula (I) include but are notlimited to:

-   -   Topoisomerase I inhibitors    -   Antimetabolites    -   Tubulin targeting agents    -   DNA binder and topo II inhibitors    -   Alkylating Agents    -   Monoclonal Antibodies.    -   Anti-Hormones    -   Signal Transduction Inhibitors    -   Proteasome Inhibitors    -   DNA methyl transferases    -   Cytokines and retinoids    -   Radiotherapy.

For the case of protein kinase A inhibitors or protein kinase Binhibitors combined with other therapies the two or more treatments maybe given in individually varying dose schedules and via differentroutes.

Where the compound of the formula (I) is administered in combinationtherapy with one or more other therapeutic agents, the compounds can beadministered simultaneously or sequentially. When administeredsequentially, they can be administered at closely spaced intervals (forexample over a period of 5-10 minutes) or at longer intervals (forexample 1, 2, 3, 4 or more hours apart, or even longer periods apartwhere required), the precise dosage regimen being commensurate with theproperties of the therapeutic agent(s).

The compounds of the invention may also be administered in conjunctionwith non-chemotherapeutic treatments such as radiotherapy, photodynamictherapy, gene therapy; surgery and controlled diets.

For use in combination therapy with another chemotherapeutic agent, thecompound of the formula (I) and one, two, three, four or more othertherapeutic agents can be, for example, formulated together in a dosageform containing two, three, four or more therapeutic agents. In analternative, the individual therapeutic agents may be formulatedseparately and presented together in the form of a kit, optionally withinstructions for their use.

A person skilled in the art would know through their common generalknowledge the dosing regimes and combination therapies to use.

Methods of Diagnosis

Prior to administration of a compound of the formula (I), a patient maybe screened to determine whether a disease or condition from which thepatient is or may be suffering is one which would be susceptible totreatment with a compound having activity against protein kinase Aand/or protein kinase B.

For example, a biological sample taken from a patient may be analysed todetermine whether a condition or disease, such as cancer, that thepatient is or may be suffering from is one which is characterised by agenetic abnormality or abnormal protein expression which leads toup-regulation of PKA and/or PKB or to sensitisation of a pathway tonormal PKA and/or PKB activity, or to upregulation of a signaltransduction component upstream of PKA and/or PKB such as, in the caseof PKB, P13K, OF receptor and PDK 1 & 2.

Alternatively, a biological sample taken from a patient may be analysedfor loss of a negative regulator or suppressor of the PKB pathway suchas PTEN. In the present context, the term “loss” embraces the deletionof a gene encoding the regulator or suppressor, the truncation of thegene (for example by mutation), the truncation of the transcribedproduct of the gene, or the inactivation of the transcribed product(e.g. by point mutation) or sequestration by another gene product.

The term up-regulation includes elevated expression or over-expression,including gene amplification (i.e. multiple gene copies) and increasedexpression by a transcriptional effect, and hyperactivity andactivation, including activation by mutations. Thus, the patient may besubjected to a diagnostic test to detect a marker characteristic ofup-regulation of PKA and/or PKB. The term diagnosis includes screening.By marker we include genetic markers including, for example, themeasurement of DNA composition to identify mutations of PKA and/or PKB.The term marker also includes markers which are characteristic of upregulation of PKA and/or PKB, including enzyme activity, enzyme levels,enzyme state (e.g. phosphorylated or not) and mRNA levels of theaforementioned proteins.

The above diagnostic tests and screens are typically conducted on abiological sample selected from tumour biopsy samples, blood samples(isolation and enrichment of shed tumour cells), stool biopsies, sputum,chromosome analysis, pleural fluid, peritoneal fluid, or urine.

Identification of an individual carrying a mutation in PKA and/or PKB ora rearrangement of TCL-1 or loss of PTEN expression may mean that thepatient would be particularly suitable for treatment with a PKA and/orPKB inhibitor. Tumours may preferentially be screened for presence of aPKA and/or PKB variant prior to treatment. The screening process willtypically involve direct sequencing, oligonucleotide microarrayanalysis, or a mutant specific antibody.

Methods of identification and analysis of mutations and up-regulation ofproteins are known to a person skilled in the art. Screening methodscould include, but are not limited to, standard methods such asreverse-transcriptase polymerase chain reaction (RT-PCR) or in-situhybridisation.

In screening by RT-PCR, the level of mRNA in the tumour is assessed bycreating a cDNA copy of the mRNA followed by amplification of the cDNAby PCR. Methods of PCR amplification, the selection of primers, andconditions for amplification, are known to a person skilled in the art.Nucleic acid manipulations and PCR are carried out by standard methods,as described for example in Ausubel, F. M. et al., eds. CurrentProtocols in Molecular Biology, 2004, John Wiley & Sons Inc., or Innis,M. A. et-al., eds. PCR Protocols: a guide to methods and applications,1990, Academic Press, San Diego. Reactions and manipulations involvingnucleic acid techniques are also described in Sambrook et al., 2001,3^(rd) Ed, Molecular Cloning: A Laboratory Manual, Cold Spring HarborLaboratory Press. Alternatively a commercially available kit for RT-PCR(for example Roche Molecular Biochemicals) may be used, or methodologyas set forth in U.S. Pat. Nos. 4,666,828; 4,683,202; 4,801,531;5,192,659, 5,272,057, 5,882,864, and 6,218,529 and incorporated hereinby reference.

An example of an in-situ hybridisation technique for assessing mRNAexpression would be fluorescence in-situ hybridisation (FISH) (seeAngerer, 1987 Meth. Enzymol., 152: 649).

Generally, in situ hybridization comprises the following major steps:(1) fixation of tissue to be analyzed; (2) prehybridization treatment ofthe sample to increase accessibility of target nucleic acid, and toreduce nonspecific binding; (3) hybridization of the mixture of nucleicacids to the nucleic acid in the biological structure or tissue; (4)post-hybridization washes to remove nucleic acid fragments not bound inthe hybridization, and (5) detection of the hybridized nucleic acidfragments. The probes used in such applications are typically labeled,for example, with radioisotopes or fluorescent reporters. Preferredprobes are sufficiently long, for example, from about 50, 100, or 200nucleotides to about 1000 or more nucleotides, to enable specifichybridization with the target nucleic acid(s) under stringentconditions. Standard methods for carrying out FISH are described inAusubel, F. M. et al., eds. Current Protocols in Molecular Biology,2004, John Wiley & Sons Inc and Fluorescence In Situ Hybridization:Technical Overview by John M. S. Bartlett in Molecular Diagnosis ofCancer, Methods and Protocols, 2nd ed.; ISBN: 1-59259-760-2; March 2004,pps. 077-088; Series: Methods in Molecular Medicine.

Alternatively, the protein products expressed from the mRNAs may beassayed by immunohistochemistry of tumour samples, solid phaseimmunoassay with microtitre plates, Western blotting, 2-dimensionalSDS-polyacrylamide gel electrophoresis, ELISA, flow cytometry and othermethods known in the art for detection of specific proteins. Detectionmethods would include the use of site specific antibodies. The skilledperson will recognize that all such well-known techniques for detectionof upregulation of PKB, or detection of PKB variants could be applicablein the present case.

Therefore all of these techniques could also be used to identify tumoursparticularly suitable for treatment with PKA and/or PKB inhibitors.

For example, as stated above, PKB beta has been found to be upregulatedin 10-40% of ovarian and pancreatic cancers (Bellacosa et al 1995, Int.J. Cancer 64, 280-285; Cheng et al 1996, PNAS 93, 3636-3641; Yuan et al2000, Oncogene 19, 2324-2330). Therefore it is envisaged that PKBinhibitors, and in particular inhibitors of PKB beta, may be used totreat ovarian and pancreatic cancers.

PKB alpha is amplified in human gastric, prostate and breast cancer(Staal 1987, PNAS 84, 5034-5037; Sun et al 2001, Am. J. Pathol. 159,431-437). Therefore it is envisaged that PKB inhibitors, and inparticular inhibitors of PKB alpha, may be used to treat human gastric,prostate and breast cancer.

Increased PKB gamma activity has been observed in steroid independentbreast and prostate cell lines (Nakatani et al 1999, J. Biol. Chem. 274,21528-21532). Therefore it is envisaged that PKB inhibitors, and inparticular inhibitors of PKB gamma, may be used to treat steroidindependent breast and prostate cancers.

EXPERIMENTAL

The invention will now be illustrated, but not limited, by reference tothe specific embodiments described in the following procedures andexamples.

The starting materials for each of the procedures described below arecommercially available unless otherwise specified.

Proton magnetic resonance (¹H NMR) spectra were recorded on a BrukerAV400 instrument operating at 400.13 MHz, in Me-d₃-OD at 27° C., unlessotherwise stated and are reported as follows: chemical shift Ε/ppm(number of protons, multiplicity where s=singlet, d=doublet, t=triplet,q=quartet, m=multiplet, br=broad). The residual protic solvent MeOH(Ε_(H)=3.31 ppm) was used as the internal reference.

In the examples, the compounds prepared were characterised by liquidchromatography and mass spectroscopy using the systems and operatingconditions set out below. Where chlorine is present, the mass quoted forthe compound is for ³⁵Cl. The operating conditions used are describedbelow.

Platform System

-   HPLC System: Waters 2795-   Mass Spec Detector: Micromass Platform LC-   PDA Detector: Waters 2996 PDA

Polar Analytical Conditions:

-   Eluent A: H₂O (0.1% Formic Acid)-   Eluent B: CH₃CN (0.1% Formic Acid)-   Gradient: 00-50% eluent B over 3 minutes-   Flow: 1.5 ml/min-   Column: Phenomenex Synergi 4μ Hydro 80A, 50x4.6 mm

MS Conditions:

-   Capillary voltage: 3.5 kV-   Cone voltage: 30 V-   Source Temperature: 120° C.-   Scan Range: 165-700 amu-   Ionisation Mode: ElectroSpray Negative, Positive or Positive &    Negative

FractionLynx System

-   System: Waters FractionLynx (dual analytical/prep)-   HPLC Pump: Waters 2525-   Injector-Autosampler: Waters 2767-   Mass Spec Detector: Waters-Micromass ZQ-   PDA Detector: Waters 2996 PDA

Acidic Analytical Conditions:

-   Eluent A: H₂O (0.1% Formic Acid)-   Eluent B: CH₃CN (0.1% Formic Acid)-   Gradient: 5-95% eluent B over 5 minutes-   Flow: 2.0 ml/min-   Column: Phenomenex Synergi 4μ Max-RP 80A, 50×4.6 mm

MS Conditions:

-   Capillary voltage: 3.5 kV-   Cone voltage: 25 V-   Source Temperature: 120° C.-   Scan Range: 125-800 amu-   Ionisation Mode: ElectroSpray Positive or ElectroSpray Positive &    Negative

LCT System

-   HPLC System: Waters Alliance 2795 Separations Module-   Mass Spec Detector: Waters/Micromass LCT-   UV Detector: Waters 2487 Dual λ Absorbance Detector

Polar Analytical Conditions:

-   Eluent A: Methanol-   Eluent B: 0.1% Formic Acid in Water-   Gradient:

Time (mins) A B 0 10 90 0.5 10 90 6.5 90 10 10 90 10 10.5 10 90 15 10 90

-   Flow: 1.0 ml/min-   Column: Supelco DISCOVERY C₁₈ 5 cm x4.6 mm i.d., 5 μm

MS Conditions:

-   Capillary voltage: 3500 v (+ve ESI), 3000 v (−ve ESI)-   Cone voltage: 40 v (+ve ESI), 50 v (−ve ESI)-   Source Temperature: 100° C.-   Scan Range: 50-1000 amu-   Ionisation Mode: +ve/−ve electrospray ESI (Lockspray™)

LCT System 2

-   HPLC System: Waters Alliance 2795 Separations Module-   Mass Spec Detector: Waters/Micromass LCT-   UV Detector: Waters 2487 Dual λ Absorbance Detector-   Analytical Conditions:-   Eluent A: Methanol-   Eluent B: 0.1% Formic Acid in Water-   Gradient:

Time (mins) A B 0 10 90 0.6 10 90 1.0 20 80 7.5 90 10 9 90 10 9.5 10 9010 10 90

-   Flow: 1 ml/min-   Column: Supelco DISCOVERY C₁₈ 5 cm×4.6 mm i.d., 5 μm

MS Conditions:

-   Capillary voltage: 3500 v (+ve ESI), 3000 v (−ve ESI)-   Cone voltage: 40 v (+ve ESI), 50 v (−ve ESI)-   Source Temperature: 100° C.-   Scan Range: 50-1000 amu-   Ionisation Mode: +ve/−ve electrospray ESI (Lockspray™)

In the examples below, the following key is used to identify the LCMSconditions used:

PS-P Platform System—polar analytical conditionsFL-A FractionLynx System—acidic analytical conditionsLCT1 LCT System 1—polar analytical conditionsLCT2 LCT System 2—polar analytical conditions

Example 1 Methyl-[1-(9H-purin-6-yl)-piperidin-4-yl]-amine 1A.{1-[9-(Tetrahydro-pyran-2-yl)-9H-purin-6-yl]-piperidin-4-yl}-carbamicacid tert-butyl ester

A mixture of 4-(N-Boc-amino)-piperidine (363.2 mg, 1.82 mmol),9-(tetrahydropyran-2-yl)-6-chloropurine (219.2 mg, 0.92 mmol), n-butanol(9 ml) and triethylamine (0.68 ml, 4.55 mmol) was heated overnight at100° C. After cooling to room temperature, the solvents were evaporatedin vacuo. The crude product was purified by flash silica columnchromatography eluting with 5% methanol in dichloromethane to afford theBoc protected compound as a white solid (352.7 mg, 0.88 mmol, 95%) LC-MS(LCT) R_(t) 6.74 [M+H]⁺ 403.

1B.Methyl-{1-[9-(tetrahydro-pyran-2-yl)-9H-purin-6-yl]-piperidin-4-yl}-carbamicacid tert-butyl ester

The{1-[9-(tetrahydro-pyran-2-yl)-9H-purin-6-yl]-piperidin-4-yl}-carbamicacid tert-butyl ester (107.7 mg, 0.27 mmol) of Example 1A was dissolvedin anhydrous dimethylformamide (1 ml) and the solution was cooled to 0°C. in an ice bath. Sodium hydride (13 mg, 60% suspension in oil, 0.33mmol) was added in small portions. The suspension was stirred vigorouslyfor an additional 20 minutes at 0° C. and then the methyl iodide (0.020ml, 0.32 mmol) was added drop wise. After stirring the reaction mixturefor 30 minutes at 0° C. this was brought to room temperature and leftstirring additionally overnight. Water (1.2 ml), followed by ethylacetate (5 ml) was added to the reaction mixture. The organic layer wasseparated, washed with water, 0.1M HCl, a saturated aqueous NaHCO₃solution, and brine before being dried and concentrated in vacuo. Thecrude product was purified by flash silica column chromatography elutingwith 5% methanol in dichloromethane to afford the required compound as awhite solid (83 mg, 0.2 mmol, 73%) LC-MS (LCT) R_(t) 7.07 [M+H]⁺ 417.

1C. Methyl-[1-(9H-purin-6-yl)-piperidin-4-yl]-amine

A solution ofmethyl-{1-[9-(tetrahydro-pyran-2-yl)-9H-purin-6-yl]-piperidin-4-yl}-carbamicacid tert-butyl ester (83 mg, 0.2 mmol), ethanol (4 ml) and 1M aqueousHCl solution (1 ml) was stirred overnight at room temperature. Thesolvents were then evaporated in vacuo and the crude product waspurified with a flash NH₂ column (2 g, 15 ml) eluting with methanol toafford the required compound (18 mg, 0.08 mmol, 39%) LC-MS (LCT) R_(t)1.27 [M+H]⁺] 233.

Example 2 Benzyl-[1-(9H-purin-6-yl)-piperidin-4-yl]-amine

By following the method of Example 1, but using benzyl bromide in placeof methyl iodide, the title compound was obtained. LC-MS (LCT) R_(t)3.17 [M+H]⁺ 309

Example 3 1-(9H-Purin-6-yl)piperidin-4-ylamine 3A.[1-(9H-Purin-6-yl)piperidin-4-yl]carbamic acid tert-butyl ester

To a mixture of 6-chloropurine (0.050 g, 0.323 mmol) and piperidin-4-ylcarbamic acid tert-butyl ester (0.129 g, 0.646 mmol) in n-butanol (3.2ml) was added triethylamine (0.225 ml, 1.617 mmol). After heating at100° C. for 20 hours, solvent was removed and the resulting solidtriturated with a DCM/methanol mix (3 ml/5 ml). Filtration gave thedesired product as a white solid (0.080 g, 78%). LC/MS: (LCT) R_(t) 5.37[M+H]⁺ 319.

3B. 1-(9H-Purin-6-yl)piperidin-4-ylamine

A solution of the purine (0.052 g, 0.163 mmol) of Example 4A in 2M HCl(2 ml) was stirred at room temperature for 2 hours, and then evaporatedto dryness. Solid phase extraction on SCX-II acidic resin, eluting withMeOH and then 1M NH₃ in MeOH, gave the deprotected amine as a whitesolid (0.034 g, 94%). LC/MS (LCT): R_(t) 1.00 [M+H]⁺ 219.

¹H NMR (MeOD) δ 1.33-1.58 (2H, m), 2.01 (2H, d, J=12.5 Hz), 2.97-3.15(1H, m), 3.15-3.32 (2H, m), 5.38 (2H, d, J=13 Hz), 8.01 (1H, s), 8.21(1H, s)

Example 4 6-(4-Aminopiperidin-1-yl)-7,9-dihydropurin-8-one 4A.[1-(8-Oxo-8,9-dihydro-7H-purin-6-yl)piperidin-4-yl]carbamic acidtert-butyl ester

By reacting 6-chloro-7,9-dihydro-purin-8-one withpiperidin-4-yl-carbamic acid tert-butyl ester according to the method ofExample 4A, the title compound was obtained. LC/MS: (LCT) R_(t) 5.68[M+H]⁺ 335.

4B. 6-(4-Aminopiperidin-1-yl)-7,9-dihydropurin-8-one

The product of Example 4A was deprotected according to the method ofExample 4B to give the title compound. LC/MS (LCT): R_(t) 1.27 [M+H]⁺235.

¹H NMR (MeOD) δ 1.39-1.60 (2H, m), 1.92-2.07 (2H, m), 2.95-3.30 (3H, m),4.30-4.45 (2H, m), 8.09 (1H, s)

Example 5 6-(4-Benzyl-4-hydroxypiperidin-1-yl)-7,9-dihydropurin-8-one5A. 6-(4-Benzyl-4-hydroxypiperidin-1-yl)-7,9-dihydropurin-8-one

4-Benzyl-1-methyl-piperidin-4-ol was reacted with6-chloro-7,9-dihydro-purin-8-one under conditions analogous to those setout in Example 3A to give the title compound LC/MS: (LCT) R_(t) 5.68[M+H]⁺ 326.

By following the method of Example 3A or methods closely similarthereto, but using 6-chloro-7,9-dihydro-purin-8-one instead of6-chloropurine, the following compounds were prepared.

¹H NMR (DMSO) δ 1.38-1.60 (4H, m), 2.70 (2H, s), 3.22-3.35 (2H, m), 3.94(2H, d, J=13 Hz), 4.44 (1H, br s), 7.18-7.33 (5H, m), 8.05 (1H, s)

Example 6 6-(piperazin-1-yl)-7,9-dihydropurin-8-one

LC/MS: (LCT) R_(t) 1.27 [M+H]⁺ 221.

¹H NMR (d₆-DMSO)

2.75 (4H, br s), 3.41 (4H, br s), 8.02 (1H, s)

Example 7(3S)-6-(3-Benzyloxymethylpiperazin-1-yl)-7,9-dihydropurin-8-one

LC/MS: (LCT) R_(t) 3.88 [M+H]⁺ 341.

¹H NMR (MeOD)

2.59-3.08 (5H, m), 3.36-3.50 (2H, m), 3.94-4.11 (2H, m), 4.46 (2H, s),7.13-7.34 (5H, m), 8.02 (1H, s)

Example 8 6-(4-Phenethylaminopiperidin-1-yl)-7,9-dihydro-purin-8-one

A mixture of 6-(4-aminopiperidin-1-yl)-7,9-dihydropurin-8-one (Example4B, 0.045 g, 0.20 mmol), phenylacetaldehyde (0.025 ml, 0.20 mmol),NaBH(OAc)₃ (0.065 g, 0.30 mmol) and acetic acid (5 drops) in1,2-dichloroethane (2 ml) and MeOH (0.5 ml) was stirred at roomtemperature for 2 hours. The solution was absorbed onto a 5 g SCX-IIacidic resin cartridge and eluted with MeOH, then 1M NH₃-MeOH. The basiceluant was concentrated. Preparative thin layer chromatography (t.l.c.),eluting with 1% NH₃ (aq)/9% MeOH/90% CH₂Cl₂ gave the product as an offwhite solid (0.007 g, 10%). LC/MS: (LCT) R_(t) 3.62 [M+H]⁺ 339.

¹H NMR (MeOD)

1.34-1.40 (2H, m), 1.92-1.97 (2H, m), 2.61-3.00 (7H, m), 4.20-4.25 (2H,m), 7.11-7.24 (5H, m), 8.01 (1H, s)

Example 96-[4-(2-Chlorobenzylamino)-piperidin-1-yl]-7,9-dihydro-purin-8-one

Following the method of Example 8 but using 2-chlorobenzaldehyde insteadof phenylacetaldehyde gave the title compound. LC/MS: (LCT) R_(t) 3.65[M+H]⁺ 359, 361.

¹H NMR (MeOD)

1.30-1.46 (2H, m), 1.95-2.00 (2H, m), 2.70-2.79 (1H, m), 2.92-3.01 (2H,m), 3.88 (2H, s), 4.18-4.23 (2H, m), 7.14-7.41 (4H, m), 8.00 (1H, s)

Example 106-[4-(3-Chlorobenzylamino)-piperidin-1-yl]-7,9-dihydro-purin-8-one

Following the method of Example 8 but using 3-chlorobenzaldehyde insteadof phenylacetaldehyde gave the title compound LC/MS: (LCT) R_(t) 3.77[M+H]⁺ 359, 361.

¹H NMR (MeOD)

1.19-1.44 (2H, m), 1.81-1.96 (2H, m), 2.61-2.76 (1H, m), 2.29-3.00 (2H,m), 4.74 (2H, s), 4.17-4.23 (2H, m), 7.15-7.27 (3H, m), 7.33 (1H, s),8.00 (1H, s)

Example 11 1-(1H-Pyrazolo[3,4-d]pyrimidin-4-yl)-piperidin-4-ylamine 11A.[1-(1H-Pyrazolo[3,4-d]pyrimidin-4-yl)-piperidin-4-yl]-carbamic acidtert-butyl ester

To a solution of 4-chloro-1H-pyrazolo[3,4-d]pyrimidine (J. Amer. Chem.Soc. 1957, 79, 6407-6413) (59 mg, 0.38 mmol) in ethanol (2 ml) was addedtriethylamine (100 μl, 0.72 mmol) and 4-(N-Boc-amino)piperidine (134 mg,0.67 mmol). The solution was heated at 80° C. for 3 hours, and thencooled to room temperature. The solution was evaporated to dryness andthe residue purified by recrystallisation (isopropanol) to yield theproduct (32 mg, 26% yield).

11B. 1-(1H-Pyrazolo[3,4-d]pyrimidin-4-yl)-piperidin-4-ylamine

To [1-(1H-pyrazolo[3,4-d]pyrimidin-4-yl)-piperidin-4-yl]-carbamic acidtert-butyl ester (28 mg, 0.088 mmol) was added HCl (1 ml, 4M solution indioxane, 4 mmol). The suspension was stirred at room temperature for 1hour, and then diluted with diethyl ether (4 ml). The ethereal layer wasdiscarded and the solid washed with a further portion of diethyl ether(2 ml). The ethereal layer was again discarded, and the resultant soliddried under high vacuum to yield the desired product (34 mg). The freebase was liberated by dissolution of this material in methanol, loadingonto an acidic resin SCX-2 cartridge, and elution from the cartridgewith ammonia in methanol. LC/MS R_(t) 0.86 [M+H]⁺ 219

Example 12 1-(7H-Pyrrolo[2,3-d]pyrimidin-4-yl)-piperidin-4-ylamine 12A.6-Amino-5-(2,2-diethoxy-ethyl)-2-mercapto-pyrimidin-4-ol

To ethanol (200 ml) was added sodium (2.05 g, 89 mmol) in smallportions. The solution was stirred until complete dissolution of thesodium metal. 2-Cyano-4,4-diethoxy-butyric acid ethyl ester (J. Chem.Soc., 1960, 131-138) (9.292 g, 40.5 mmol) was then added as a solutionin ethanol (50 ml), followed by addition of thiourea (3.08 g, 40.4mmol). The solution was heated at 85° C. for 18 hours, and then cooledto room temperature. The solution was concentrated, and saturatedaqueous ammonium chloride solution (150 ml) was added. The mixture wasstirred at room temperature for 18 hours, after which time the solid wascollected by filtration, and washed with water (20 ml) to yield theproduct (3.376 g, 36%).

12B. 6-Amino-5-(2,2-diethoxy-ethyl)-pyrimidin-4-ol

To a suspension of6-amino-5-(2,2-diethoxy-ethyl)-2-mercapto-pyrimidin-4-ol (1.19 g, 4.6mmol) in water (50 ml) was added Raney nickel (Aldrich Raney 2800nickel, 4.8 ml). The mixture was heated at reflux for 1 hour, and thenthe hot solution was filtered through Celite®. The nickel residue waswashed with further water (100 ml), and these washings were filteredthrough Celite. The aqueous filtrate was evaporated to dryness to yieldthe title product (0.747 g, 71%).

12C. 7H-Pyrrolo[2,3-d]pyrimidin-4-ol

This compound was prepared as described in J. Chem. Soc., 1960, pp.131-138.

12D. 4-Chloro-7H-pyrrolo[2,3-d]pyrimidine

To 7H-pyrrolo[2,3-d]pyrimidin-4-ol (0.425 g, 3.14 mmol) was addedphosphorus oxychloride (4 ml). The mixture was heated at reflux for 90minutes and then cooled to room temperature. The solution was pouredonto cracked ice, and extracted with chloroform (3×50 ml) and ethylacetate (100 ml). The extracts were then dried and concentrated, and theresidue obtained triturated with hot ethyl acetate (200 ml) to yield thetitle compound (0.204 g, 42%).

12E. [1-(7H-Pyrrolo[2,3-d]pyrimidin-4-yl)-piperidin-4-yl]-carbamic acidtert-butyl ester

To a solution of 4-chloro-7H-pyrrolo[2,3-a]pyrimidine (74 mg, 0.48 mmol)in ethanol (1 ml) was added triethylamine (200 μl, 1.43 mmol) and4-N-Boc-aminopiperidine (106 mg, 0.53 mmol). The solution was heated at80° C. for 4 hours, and then cooled to room temperature. The precipitatewas collected by filtration and washed with ethanol (2 ml), then driedunder vacuum to yield the product (57 mg, 36%). LC/MS (LCT) R_(t) 4.57[M+H]⁺ 318

12F. 1-(7H-Pyrrolo[2,3-d]pyrimidin-4-yl)-piperidin-4-ylamine

To [1-(7H-Pyrrolo[2,3-d]pyrimidin-4-yl)-piperidin-4-yl]-carbamic acidtert-butyl ester (57 mg, 0.18 mmol) was added HCl (1 ml, 4M solution indioxane, 4 mmol). The solution was stirred at room temperature for 1hour, and then diethyl ether was added (4 ml). The ethereal layer wasdiscarded and the solid triturated with a further portion of ether (4ml) and dried [product mass 27 mg]. A portion of the product wasdissolved in methanol, absorbed onto an acidic resin SCX-2 cartridge,and the free base was eluted with 1M ammonia in methanol. LC/MS (LCT)R_(t) 0.81 [M+H]⁺ 218

Example 13 1-(1H-Pyrrolo[2,3-b]pyridin-4-yl)-piperidin-4-ylamine 13A.1H-Pyrrolo[2,3-b]pyridine 7-oxide

To a solution of 7-azaindole (3.04 g, 25 mmol) in DME (60 ml) was added77% m-chloroperoxybenzoic acid (6.8 g, 12 mmol). The resulting yellowsolution was stirred at room temperature for 1.5 hours, during whichtime the product precipitated. The mixture was filtered and the solidwashed with diethyl ether to give 7-hydroxy-1H-pyrrolo[2,3-b]pyridiniumm-chlorobenzoate (3.9 g, 13.3 mmol, 53%). A suspension of7-hydroxy-1H-pyrrolo[2,3-b]pyridinium m-chlorobenzoate (3.9 g, 13.3mmol) in water (35 ml) was basified to pH 11 with a saturated aqueoussolution of potassium carbonate. The 1H-pyrrolo[2,3-b]pyridine 7-oxidestarted to precipitate. The mixture was kept in the fridge overnight forfurther precipitation to occur. The solid was filtered, washed withhexane and diethyl ether to afford the required oxide as a white solid(1.35 g, 10 mmol, 40%). LC/MS (LCT) R_(t) 2.60 [M+H]⁺135.

13B. 4-Chloro-1H-pyrrolo[2,3-b]pyridine

A mixture of 1H-pyrrolo[2,3-b]pyridine 7-oxide (1.35 g, 10 mmol) andphosphorous oxychloride (7.6 ml) was refluxed for 6 hours. After coolingdown the reaction mixture to room temperature, ice (90 ml) was added andthe mixture was basified to pH 9 with a saturated aqueous solution ofpotassium carbonate. The brownish solid was filtered, washed with water,hexane and diethyl ether (547 mg, 3.6 mmol, 36%). LC/MS (LCT) R_(t) 5.74[M+H]⁺ 153, 155.

13C. [1-(1H-Pyrrolo[2,3-b]pyridin-4-yl-piperidin-4-yl]-carbamic acidtert-butyl ester

A mixture of 4-chloro-1H-pyrrolo[2,3-b]pyridine (100 mg, 0.64 mmol),4-N-(Boc-amino)-piperidine (453 mg, 2.24 mmol) andN-methyl-pyrrolidinone (0.2 ml) was microwaved for 1 hour at 160° C. Thesolution was diluted with methanol and purified through an SCX acidicresin cartridge eluting initially with methanol and then with a 3Msolution of ammonia in methanol. The crude product was further purifiedby flash silica column chromatography eluting with 8% methanol indichloromethane to afford the required compound (56 mg, 0.18 mmol, 28%).LC/MS (LCT) R_(t) 14.64 [M+H]⁺ 317.

13D. 1-(1H-Pyrrolo[2,3-b]pyridin-4-yl)-piperidin-4-ylamine

Trifluoroacetic acid (1 ml) was added dropwise to a solution of[1-(1H-pyrrolo[2,3-b]pyridin-4-yl)-piperidin-4-yl]-carbamic acidtert-butyl ester (19 mg, 0.06 mmol) in dichloromethane (1 ml), withstirring and cooling on ice. After 2.5 hours, the solvents wereconcentrated in vacuo and the crude product was purified on a basicresin NH₂ cartridge (2 g, 15 ml) eluting with methanol to afford therequired compound (12.5 mg, 0.058 mmol, 96%). LC-MS (LCT) R_(t) 0.95[M+H]⁺ 217

Example 14C-[4-(4-Chloro-phenyl)-1-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-piperidin-4-yl]-methylamine14A. 4-(4-Chlorophenyl)-4-cyanopiperidin-1-carboxylic acid tert-butylester

4-Chlorophenylacetonitrile was reacted with three equivalents of sodiumhydride and one equivalent ofN-tert-butyloxycarbonyl-bis-(2-chloroethyl)amine in DMF, initially atroom temperature and then at 60° C. to give, after work up, theN-protected piperidine nitrile title compound.

14B. 4-Aminomethyl-4-(4-chlorophenyl)piperidine-1-carboxylic acidtert-butyl ester

To a solution of 4-(4-chlorophenyl)-4-cyanopiperidin-1-carboxylic acidtert-butyl ester (0.355 g, 1.107 mmol) in ethanol (20 ml) at roomtemperature was added Raney Nickel (Raney Nickel 2800, 1 ml) and thesuspension stirred under 1 atmosphere of hydrogen for 20 hours. Thesuspension was filtered through celite and the filtrate concentrated togive the amine as an oil (0.258 g, 69%). LC/MS: (LCT) R_(t) 5.02[M—Bu^(t)—NH₂]⁺ 324.

14C. C-[4-(4-chlorophenyl)piperidin-4-yl]methylamine hydrochloride

To a solution of 4-aminomethyl-4-(4-chlorophenyl)piperidine-1-carboxylicacid tert-butyl ester (0.258 g, 0.794 mmol) in methanol (10 ml) at roomtemperature was added 2M hydrochloric acid (10 ml). After 18 h thesolution was concentrated to dryness to give the amine salt as a whitefoam (0.232 g, 98%). ¹H NMR (MeOD) δ 2.10-2.22 (2H, m), 2.60-2.66 (2H,m), 2.92-3.02 (2H, m), 3.24 (2H, s), 3.37-3.46 (2H, m), 7.51-7.59 (4H,m).

14D.C-[4-(4-Chloro-phenyl)-1-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-piperidin-4-yl]-methylamine

A solution of C-[4-(4-chlorophenyl)piperidin-4-yl]methylaminehydrochloride (0.060 g, 0.202 mmol),4-chloro-7H-pyrrolo[2,3-d]pyrimidine (0.031 g, 0.202 mmol) andtriethylamine (0.14 ml, 1.008 mmol) in n-butanol (2 ml) was heated at100° C. for 2 days. The reaction mixture was evaporated to dryness andpurified by Solid phase extraction on SCX-II acidic resin, eluting withMeOH then 1M NH₃ in MeOH, to give the crude amine. Purification bysilica column chromatography (15%-20% methanol in DCM) gave an off whitefoam solid (0.018 g, 26%). LC/MS (LCT): R_(t) 3.60 [M+H]⁺ 341.

¹H NMR (MeOD) δ 1.87-1.98 (2H, m), 2.33-2.43 (2H, m), 2.82, (2H, s),3.45-3.55 (2H, m), 4.43-4.46 (2H, m), 6.65 (1H, d, J=4 Hz), 7.13 (1H, d,J=4 Hz), 7.44-7.52 (4H, m), 8.13 (1H, s)

Example 15C-[4-(4-Chloro-phenyl)-1-(9H-purin-6-yl)-piperidin-4-yl]-methylamine

The product of Example 14C was reacted with 6-chloropurine following amethod analogous to the method of Example 2 to give the title compound.LC/MS: (LCT) R_(t) 3.91 [M+H]⁺ 342.

¹H NMR (MeOD) δ 1.85-1.95 (2H, m), 3.31-2.46 (2H, m), 2.83 (2H, s),3.57-3.70 (2H, m), 4.85-5.00 (2H, m), 7.45-7.57 (4H, m), 8.01 (1H, s),8.20 (1H, s)

Example 16 4-Benzyl-1-(9H-purin-6-yl)piperidin-4-ylamine 16A.4-Benzylpiperidine-1,4-dicarboxylic acid 1-tert-butyl ester 4-methylester

To a solution of isopropylamine (1.34 ml, 9.559 mmol) in THF (40 ml) at0° C. was added n-butyllithium (3.65 ml of a 2.5M sol. In hexanes, 9.125mmol). The resulting LDA solution was added via cannula to a solution ofpiperidine-1,4-dicarboxylic acid 1-tert-butyl ester 4 methyl ester (2.11g, 8.690 mmol) in THF (40 ml) and HMPA (8 ml) at −78° C. and stirringcontinued for 1 hour. Benzyl bromide (1.19 ml, 9.994 mmol) in THF (5 ml)was then added and the solution warmed to room temperature over 2 hours.After stirring for 18 h, saturated aqueous ammonium chloride (200 ml)was added and the aqueous phase extracted with diethyl ether (2×100 ml).Organic phases were combined, dried over magnesium sulphate andconcentrated to dryness. Purification by silica column chromatography(0.5% methanol in DCM) gave the ester as an oil (1.816 g, 63%). LC/MS:(LCT) R_(t) 7.67 [M+H]⁺ 333.

16B. 4-Benzylpiperidine-1,4-dicarboxylic acid mono-tert-butyl ester

To a solution of 4-benzylpiperidine-1,4-dicarboxylic acid 1-tert-butylester 4-methyl ester (1.772 g, 5.315 mmol) in dioxane (24 ml), methanol(12 ml), and water (12 ml) at room temperature was added lithiumhydroxide monohydrate (4.460 g, 106.292 mmol). After stirring at 50° C.for 2 days the solution was acidified to pH 6 using 2M HCl and theresulting white precipitate extracted with diethyl ether (2×100 ml). Theorganic phases were combined, dried over sodium sulphate andconcentrated to dryness to give the acid as a white solid (1.477 g,87%). LC/MS (LCT): R_(t) 7.37 [M+H]⁺ 319.

16C. 4-Benzyl-1-(9H-purin-6-yl)piperidin-4-ylamine

To a mixture of acid (1.467 g, 4.593 mmol) and triethylamine (1.28 ml,9.186 mmol) in THF (46 ml) at −15° C. was added isobutyl chloroformate(0.901 ml, 6.890 mmol). After 1 h a solution of sodium azide (0.597 g,9.186 mmol) in water (10 ml) was added and the solution warmed to roomtemperature overnight. Water (100 ml) was added and the aqueous phaseextracted with diethyl ether (3×50 ml). Organic phases were combined,washed with saturated sodium bicarbonate (50 ml) and dried over sodiumsulphate. Toluene (100 ml) was added and the overall volume reduced toapproximately 90 ml. The resulting solution was warmed to 90° C. for 2h, then cooled and added to 10% hydrochloric acid (70 ml). The biphasicmixture was warmed to 90° C. for 24 hours. The organic phase wasseparated and concentrated to dryness to give the crude amine salt (883mg), which was used without further purification.

A portion of amine salt (0.044 g, 0.1680 mmol), 6-chloropurine (0.026 g,0.1680 mmol) and triethylamine (0.117 ml, 0.8399 mmol) in n-butanol (1.7ml) was heated to 100° C. for 24 hours. The mixture was concentrated todryness then washed with methanol (5 ml), with the resulting soliddissolved in 2M NH₃ in methanol and passed through a —NH₂ isolute column(2 g). Concentration of the filtrate gave the amine as a solid (0.037 g,71% from amine salt). LC/MS (LCT): R_(t) 3.89 [M+H]⁺ 308.

¹H NMR (DMSO) δ 1.51-1.78 (4H, m), 2.88 (2H, s), 3.97-4.21 (4H, m),7.25-7.40 (5H, m), 8.12 (1H, s), 8.20 (1H, s)

Example 174-(4-Chlorobenzyl)-1-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)piperidin-4-ylamine

17A. 4-(4-Chlorobenzyl)piperidine-1,4-dicarboxylic acid 1-tert-butylester 4-methyl ester

To a solution of isopropylamine (3.71 ml, 26.45 mmol) in THF (110 ml) at0° C. was added n-butyllithium (10.1 ml of a 2.5M solution in hexanes,25.25 mmol). The resulting LDA solution was added via cannula to asolution of piperidine-1,4-dicarboxylic acid 1-tert-butyl ester 4-methylester (5.85 g, 24.04 mmol) in THF (110 ml) and HMPA (20 ml) at −78° C.and stirring was continued for 1 hour. 4-Chlorobenzyl chloride (6.4 ml,50.49 mmol) in THF (20 ml) was added and the solution was warmed to roomtemperature over 2 hours. After stirring for 18 hours, saturated aqueousammonium chloride (500 ml) was added and the aqueous phase was extractedwith diethyl ether (2×200 ml). The organic phases were combined, driedover magnesium sulphate and concentrated to dryness. Purification bysilica column chromatography (0.5% methanol in DCM) gave the ester as anoil (3.03 g, 34%). LC-MS (LCT1) m/z 390 [M+Na⁺], R_(t) 8.02 min.

17B. 4-(4-Chlorobenzyl)piperidine-1,4-dicarboxylic acid mono-tert-butylester

To a solution of 4-(4-chlorobenzyl)piperidine-1,4-dicarboxylic acid1-tert-butyl ester 4-methyl ester (1.515 g, 4.117 mmol) in dioxane (20ml), methanol (10 ml) and water (10 ml) at room temperature was addedlithium hydroxide monohydrate (3.455 g, 82.341 mmol). After stirring at50° C. for 2 days the solution was acidified to pH 6 with 2M HCl and theresulting white precipitate was extracted with diethyl ether (2×100 ml).The organic phases were combined, dried over sodium sulphate andconcentrated to dryness, to give the acid as a white solid (1.460 g,100%). LC-MS (LCT) m/z 376 [M+Na⁺], R_(t) 7.62 min.

17C. 4-(4-Chlorobenzyl)piperidin-4-yl amine

To a mixture of the acid (1.46 g, 4.126 mmol) and triethylamine (1.15ml, 8.252 mmol) in THF (41 ml) at −15° C. was added isobutylchloroformate (0.812 ml, 6.189 mmol). After 1 hour, a solution of sodiumazide (0.536 g, 8.252 mmol) in water (10 ml) was added and the solutionwas warmed to room temperature overnight. Water (100 ml) was added andthe aqueous phase was extracted with diethyl ether (3×50 ml). Theorganic phases were combined, washed with saturated sodium bicarbonate(50 ml) and dried over sodium sulphate. Toluene (100 ml) was added andthe overall volume was reduced to approximately 90 ml. The resultingsolution was warmed to 90° C. for 2 h, then cooled and added to 10%hydrochloric acid (70 ml). The biphasic mixture was warmed to 90° C. for24 hours. The organic phase was separated and concentrated to dryness togive the crude amine salt (1.109 g).

The crude amine salt was dissolved in 2M NaOH (20 ml) and di-tert-butyldicarbonate (1.61 g, 7.391 mmol) added. After 2 days the aqueous phasewas extracted with diethyl ether (2×50 ml). The organic phases werecombined, washed with 1M HCl (20 ml), saturated sodium bicarbonate (20ml) and brine (20 ml), then dried over magnesium sulphate andconcentrated. Purification by column chromatography (50% diethyl etherin hexanes) gave the doubly BOC-protected amine (0.685 g), which wassubsequently deprotected by stirring with 4M HCl in dioxane (10 ml) andmethanol (10 ml) at room temperature for 2 days. Concentration gave thedesired amine as the bis-hydrochloride salt (0.492 g, 40% from acid).

¹H NMR (MeOD) δ 7.48-7.44 (m, 2H), 7.35-7.32 (m, 2H), 3.53-3.47 (4H, m),3.21 (s, 2H), 2.18-2.13 (4H, m).

17D.4-(4-Chlorobenzyl)-1-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)piperidin-4-ylamine

A solution of 4-(4-chlorobenzyl)piperidin-4-yl amine hydrochloride(0.060 g, 0.2016 mmol), 4-chloro-7H-pyrrolo[2,3-d]pyrimidine (0.031 g,0.2016 mmol) and triethylamine (0.140 ml, 1.0079 mmol) in n-butanol (2.0ml) was heated to 100° C. for 24 hours. Concentration and purificationby preparative silica TLC gave a white solid (0.034 g, 49%). LC-MS (LCT)m/z 342 [M+H⁺], R_(t) 3.25 min.

¹H NMR (MeOD) δ 1.53-1.94 (4H, m), 2.81 (2H, s), 3.75-3.90 (2H, m),4.21-4.41 (2H, m), 6.64 (1H, d, J=4 Hz), 7.13 (1H, J=4 Hz), 7.27-7.36(4H, m), 8.14 (1H, s)

Example 18 4-(4-Chlorobenzyl)-1-(9H-purin-6-yl)piperidin-4-yl amine

The title compound was prepared as described in Example 17 using6-chloropurine in place of 4-chloro-7H-pyrrolo[2,3-d]pyrimidine. LC-MS(LCT) m/z 343 [M+H⁺], R_(t) 4.02 min.

¹H NMR (MeOD) δ 1.40-1.74 (4H, m), 2.68 (2H, s), 3.79-3.89 (2H, m),4.59-4.77 (2H, m), 7.10-7.23 (4H, m), 7.89 (1H, s), 8.08 (1H, s)

Example 19C-[4-(4-Chlorobenzyl)-1-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)piperidin-4-yl]methylamine

19A. 4-(4-Chlorobenzyl)-4-cyanopiperidine-1-carboxylic acid tert-butylester

To a solution of isopropylamine (1.53 ml, 10.94 mmol) in THF (30 ml) at−78° C. was added n-butyllithium (4.38 ml of a 2.5M solution in hexanes,10.938 mmol). After 10 minutes, a solution of4-cyanopiperidine-1-carboxylic acid tert-butyl ester in THF (12 ml) wasadded. After a further 1 hour, a solution of 4-chlorobenzyl chloride(1.84 g, 11.4 mmol) in THF (5 ml) was added and the solution warmed toroom temperature over 15 hours. Water (150 ml) was added and the aqueousphase extracted with diethyl ether (150 ml). The organic phase was driedover magnesium sulphate and concentrated to give a crude solid that waspurified by recrystallisation from diethyl ether/hexane in two batchesto give the product as a white solid (2.650 g, 83%). LC-MS (LCT2) m/z357 [M+Na⁺], 235 [M-Boc]⁺, R_(t) 8.02 min.

19B. C-[4-(4-Chlorobenzyl)piperidin-4-yl]methyl amine

To a solution of 4-(4-chlorobenzyl)-4-cyanopiperidine-1-carboxylic acidtert-butyl ester (0.500 g, 1.493 mmol) in methanol (3 ml) was added 4MHCl in dioxane (10 ml). After stirring for 19 hours, the solution wasconcentrated to give the deprotected amine as the hydrochloride salt(0.405 g).

The amine salt was dissolved in 1M BH₃.THF in THF (15 ml, 15 mmol) atroom temperature and stirred for 2 days. The reaction was quenched withmethanol (10 ml), concentrated, redissolved in methanol (10 ml) and 4MHCl in dioxane (20 ml) and the resulting solution refluxed for 6 hours.Concentration and purification by SCX-2 Isolute column (5 g), elutingwith 1M NH₃/MeOH, gave the desired amine, which was converted to thebis-hydrochloride salt by dissolving in 2M aqueous HCl (6 ml) andmethanol (6 ml) followed by concentration to give the product as a whitesolid (0.285 g, 61%). ¹H NMR (MeOD)-free amine-δ 7.31-7.28 (m, 2H),7.20-7.17 (m, 2H), 2.94-2.75 (m, 4H), 2.70 (s, 2H), 2.52 (s, 2H),1.45-1.41 (m, 4H).

19C.C-[4-(4-Chlorobenzyl)-1-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)piperidin-4-yl]methylamine

A solution of C-[4-(4-chlorobenzyl)piperidin-4-yl]methyl aminehydrochloride (0.063 g, 0.2016 mmol),4-chloro-7H-pyrrolo[2,3-d]pyrimidine (0.031 g, 0.2016 mmol) andtriethylamine (0.140 ml, 1.0079 mmol) in n-butanol (2.0 ml) was heatedto 100° C. for 24 hours. Concentration and purification by SCX-2 Isolutecolumn (2 g), eluting with 1M NH₃/MeOH, followed by silica columnchromatography (15% methanol in DCM) gave a white solid (0.040 g, 56%).LC-MS (LCT2) m/z 356 [M+H⁺], R_(t) 2.97 min.

¹H NMR (MeOD) δ 1.61 (4H, br s), 2.62 (2H, s), 2.79 (2H, s), 3.90-3.94(2H, m), 4.05-4.08 (2H, m), 6.63 (1H, d, J=3 Hz), 7.12 (J=3 Hz),7.22-7.32 (4H, m), 8.13 (1H, s)

Example 206-[4-Aminomethyl-4-(4-chlorophenyl)piperidin-1-yl]-7,9-dihydropurin-8-one

The title compound was prepared as described in Example 14 using6-chloro-8-oxopurine in place of 4-chloro-7H-pyrrolo[2,3-d]pyrimidine.LC-MS (LCT) m/z 359 [M+H⁺], R_(t) 4.09 min.

¹H NMR (MeOD) δ 1.84-1.98 (2H, m), 2.30-2.42 (2H, m), 2.82 (2H, s),3.24-3.40 (2H, m), 3.94-4.10 (2H, m), 7.42-7.49 (4H, m), 8.11 (1H, s)

Example 21C-[4-(4-Chlorophenyl)-1-(1H-pyrrolo[2,3-b]pyridin-4-yl)piperidin-4-yl]methylamine

The title compound was prepared in a similar manner to Example 14, using4-chloro-7-azaindole in place of 4-chloro-7H-pyrrolo[2,3-d]pyrimidine,with NMP as solvent and microwave heating at 155° C. LC-MS (LCT2) m/z341 [M+H⁺], R_(t) 2.85 min.

¹H NMR (MeOD) δ 1.98-2.13 (2H, m), 2.37-2.49 (2H, m), 2.84 (2H, s),3.18-3.28 (2H, m), 3.76-3.90 (2H, m), 6.46 (1H, d, J=6 Hz), 6.54 (1H, d,J=3.5 Hz), 7.18 (1H, d, J=3.5 Hz), 7.42-7.51 (4H, m), 7.91 (1H, d, J=6Hz)

Example 226-[4-Aminomethyl-4-(4-chlorophenyl)piperidin-1-yl]-7-ethyl-7,9-dihydro-purin-8-one

22A. Ethyl(4,6-dichloropyrimidin-5-yl)amine

Sodium hydride (55%, 0.17 g, 4.0 mmol) was added in a single portion toa solution of (4,6-dichloropyrimidin-5-yl)amine (0.61 g, 3.72 mmol) andethyl iodide (0.30 mL, 3.8 mmol) in dry DMF (3 mL) at room temperature.The suspension was stirred for 18 hours, then diluted with saturatedaqueous ammonium chloride (5 mL) and water (20 mL). The mixture wasextracted with diethyl ether (30 mL), and the extract was dried,filtered and concentrated. Flash column chromatography on silica,eluting with 10% ethyl actetate-hexanes, gaveethyl(4,6-dichloropyrimidin-5-yl)amine (0.321 g, 1.67 mmol, 45%). LC-MS(LCT2) m/z 192, 194 [M+H⁺], R_(t) 6.07 min.

22B N⁵-Ethyl-6-chloropyrimidine-4,5-diamine

A suspension of ethyl(4,6-dichloropyrimidin-5-yl)amine (0.31 g, 1.61mmol) and concentrated aqueous ammonia (10 mL) in ethanol (3 mL) washeated to 100° C. in a sealed tube for 16 hours. The solution was cooledand evaporated to dryness. The residue was partitioned between ethylacetate (20 mL) and dilute brine (10 mL). The organic layer was dried,filtered and concentrated to giveN⁵-ethyl-6-chloropyrimidine-4,5-diamine (0.214 g, 1.24 mmol, 77%) as awaxy solid. LC-MS (LCT2) m/z 173, 175 [M+H⁺], R_(t) 3.97.

22C. 7-Ethyl-6-chloro-7,9-dihydropurin-8-one

A solution of N⁵-ethyl-6-chloropyrimidine-4,5-diamine (0.21 g, 1.22mmol) and 1,1-carbonyldiimidazole (0.40 g, 2.44 mmol) in 1,4-dioxane (5mL) was degassed, flushed with nitrogen and refluxed under nitrogen for22 h. The solution was cooled and partitioned between ethyl acetate (15mL), 1M hydrochloric acid (10 mL) and brine (5 mL). The organic layerwas dried, filtered and concentrated to give7-ethyl-6-chloro-7,9-dihydropurin-8-one (0.146 g, 0.735 mmol, 60%) as ayellow solid. LC-MS (LCT2) m/z 199, 201 [M+H⁺], R_(t) 4.62 min.

22D.6-[4-Aminomethyl-4-(4-chlorophenyl)piperidin-1-yl]-7-ethyl-7,9-dihydro-purin-8-one

A solution of 7-benzyl-6-chloro-7,9-dihydropurin-8-one (0.015 g, 0.075mmol), C-[4-(4-chlorophenyl)piperidin-4-yl]methylamine bis hydrochloride(0.025 g, 0.085 mmol) and triethylamine (0.11 mL, 0.85 mmol) inn-butanol (0.5 mL) was heated at 150° C. in a microwave reactor for 3 h.The cooled mixture was partitioned between ethyl acetate (30 mL) andwater (5 mL) and the organic layer was dried, filtered and concentrated.Purification on SCX-II acid resin, eluting with methanol then 1Mammonia/methanol, gave6-[4-aminomethyl-4-(4-chlorophenyl)piperidin-1-yl]-7-ethyl-7,9-dihydropurin-8-oneas a cream solid (0.016 g, 0.041 mmol, 56%). LC-MS (LCT2) m/z 387[M+H⁺], R_(t) 14.18 min.

Example 23C-[4-(4-Chlorobenzl)-1-(9H-purin-6-yl)piperidin-4-yl]methylamine

The title compound was prepared as described in Example 19 using6-chloropurine in place of 4-chloro-7H-pyrrolo[2,3-d]pyrimidine. LC-MS(LCT2) m/z 357 [M+H⁺], R_(t) 4.07 min.

¹H NMR (MeOD) δ 1.57-1.62 (4H, m), 2.64 (2H, s), 2.82 (2H, s), 4.20-4.28(2H, m), 4.39-4.47 (2H, m), 7.21-7.33 (4H, m), 7.98 (1H, s), 8.18 (2H,s)

Example 244-(4-Chlorophenyl)-1-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)piperidine-4-carbonitrile

24A. 4-(4-Chlorophenyl)piperidine-4-carbonitrile

To a solution of 4-(4-chlorophenyl)-4-cyanopiperidine-1-carboxylic acidtert-butyl ester (1.000 g, 3.12 mmol) in methanol (5 ml) at rt was added4M HCl in dioxane (15 ml). After stirring for 20 h the solution wasconcentrated to give the deprotected amine as the hydrochloride salt(0.785 g, 98%). LC-MS (LCT2) m/z 221 [M+H⁺], R_(t) 12.84 min.

24B.4-(4-Chlorophenyl)-1-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)piperidine-4-carbonitrile

A solution of 4-(4-chlorophenyl)piperidine-4-carbonitrile hydrochloride(0.055 g, 0.2155 mmol), 4-chloro-7H-pyrrolo[2,3-d]pyrimidine (0.033 g,0.2155 mmol) and triethylamine (0.150 ml, 1.0775 mmol) in n-butanol (2.0ml) was heated to 100° C. for 2 days. Concentration and trituration withmethanol (3 ml) gave a white solid (0.058 g, 80%). LC-MS (LCT2) m/z 338[M+H⁺], R_(t) 16.17 min.

¹H NMR (DMSO) δ 2.03-2.15 (2H, m), 2.26-2.31 (2H, m), 3.36-3.41 (2H, m),4.91 (2H, d, J=14 Hz), 6.66-6.68 (1H, m), 7.23-7.25 (1H, m), 7.50-7.63(4H, m), 8.21 (1H, s)

Example 254-(4-Chlorophenyl)-1-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)piperidin-4-ylamine

25A. 4-(4-Chlorophenyl)piperidine-1,4-dicarboxylic acid mono-tert-butylester

A solution of 4-(4-chlorophenyl)-4-cyanopiperidine-1-carboxylic acidtert-butyl ester (0.683 g, 2.129 mmol) in 6M HCl (20 ml) was refluxedfor 4 days. The solution was cooled, basified with NaOH anddi-tert-butyl dicarbonate (0.558 g, 2.555 mmol) added. After stirringfor 24 h the solution was extracted with diethyl ether (2×75 ml). Theorganic phases were combined, washed with brine (50 ml), dried overmagnesium sulphate and concentrated. Purification by silica columnchromatography (5% methanol in DCM) gave the acid as a white foam (0.339g, 47%). LC-MS (LCT2) m/z 362 [M+Na⁺], R_(t) 8.17 min.

25B. 4-(4-Chlorophenyl)piperidin-4-yl amine

The title compound was prepared using the method described for Example17C. ¹H NMR (MeOD) δ 7.74-7.70 (m, 2H), 7.65-7.61 (m, 2H), 3.61-3.52 (m,2H), 3.07-2.93 (m, 4H), 2.56-2.44 (m, 2H).

25C.4-(4-Chlorophenyl)-1-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)piperidin-4-ylamine

A solution of 4-(4-chlorophenyl)piperidin-4-yl amine hydrochloride(0.030 g, 0.1058 mmol), 4-chloro-7H-pyrrolo[2,3-d]pyrimidine (0.016 g,0.1058 mmol) and triethylamine (0.074 ml, 0.5289 mmol) in n-butanol (1.0ml) was heated to 100° C. for 2 days. Concentration and purification bySCX-2 Isolute column (2 g), eluting with 1M NH₃/MeOH, followed by silicacolumn chromatography (20% methanol in DCM) gave a white solid (0.026 g,74%). LC-MS (LCT2) m/z 328 [M+H⁺], R_(t) 2.59 min.

¹H NMR (MeOD) δ 1.90-1.95 (2H, m), 2.18-2.34 (2H, m), 3.93-4.03 (2H, m),4.20-4.29 (2H, m), 6.67 (1H, d, J=4 Hz), 7.15 (1H, d, J=4 Hz), 7.16-7.58(4H, m), 8.16 (1H, s)

Example 26C-[4-(3-Chlorophenyl)-1-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)piperidin-4-yl]methylamine

The title compound was prepared using the methods described in Example14. LC-MS (LCT2) m/z 342 [M+H⁺], R_(t) 2.55 min.

¹H NMR (MeOD) δ 1.86-1.91 (2H, m), 2.30 (2H, d, J=14 Hz), 2.78 (2H, s),3.43-3.50 (2H, m), 4.29-4.33 (2H, m), 6.59-6.60 (1H, m), 7.10-7.11 (1H,m), 7.27-7.29 (1H, m), 7.36-7.41 (2H, m), 7.47 (1H, s), 8.13 (1H, s)

Example 27C-[4-(3-Chlorophenyl)-1-(9H-purin-6-yl)piperidin-4-yl]methylamine

The title compound was prepared using the methods described in describedin Examples 14 and 15. LC-MS (LCT2) m/z 343 [M+H⁺], R_(t) 13.60 min.

¹H NMR (DMSO) δ 1.81-1.90 (2H, m), 2.12-2.19 (2H, m), 2.70 (2H, s), 3.33(2H, br s), 3.52 (2H, br s), 4.69 (2H, br s), 7.29-7.45 (4H, m), 8.10(1H, s), 8.19 (1H, s)

Example 28C-[4-(3,4-Dichlorophenyl)-1-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)piperidin-4-yl]methylamine

The title compound was prepared using the methods described in Example14. LC-MS (LCT2) m/z 376 [M+H⁺], R_(t) 3.29 min.

¹H NMR (DMSO) δ 1.83-1.91 (2H, m), 2.16-2.25 (2H, m), 2.78 (2H, s),3.39-3.47 (2H, m), 4.20-4.25 (2H, m), 6.58 (1H, d, J=3 Hz), 7.17 (1H, d,J=3 Hz), 7.41-7.45 (1H, m), 7.57-7.65 (2H, m), 8.13 (1H, s)

Example 29C-[4-(3,4-Dichlorophenyl)-1-(9H-purin-6-yl)piperidin-4-yl]methylamine

The title compound was prepared using the methods described in Examples14 and 15. LC-MS (LCT2) m/z 377 [M+H⁺], R_(t) 4.37 min.

¹H NMR (DMSO) δ 1.88-1.97 (2H, m), 2.23-2.28 (2H, m), 3.00 (2H, s), 3.66(2H, br s), 7.73 (2H, br s), 7.46-7.50 (1H, m), 7.58-7.73 (2H, m), 8.09(1H, s), 8.21 (1H, s)

Example 30C-[1-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-4-trifluoromethoxyphenyl)piperidin-4-yl]methylamine

The title compound was prepared using the methods described in Example14. LC-MS (LCT2) m/z 392 [M+H⁺], R_(t) 3.25 min.

¹H NMR (MeOD) δ 1.17-1.21 (2H, m), 1.61-1.64 (2H, m), 2.08 (2H, s),2.73-2.78 (2H, m), 3.59-3.63 (2H, m), 5.88 (1H, d, J=3.5 Hz), 6.38 (1H,d, J=3.5 Hz), 6.59-6.61 (2H, m), 6.83-6.84 (2H, m), 7.38 (1H, s)

Example 31C-[1-(9H-Purin-6-yl)-4-(4-trifluoromethoxyphenyl)piperidin-4-yl]methylamine

The title compound was prepared using the methods described in Examples14 and 15. LC-MS (LCT2) m/z 393 [M+H⁺], R_(t) 4.30 min.

¹H NMR (MeOD) δ 1.88-1.99 (2H, m), 2.35-2.41 (2H, m), 2.83 (2H, s),3.62-3.71 (2H, m), 4.79-4.95 (2H, m), 7.34-7.57 (2H, m), 7.57-7.66 (2H,m), 7.99 (1H, s), 8.20 (1H, s)

Example 32C-[1-(7H-Pyrrolo[2,3-d]pyrimidin-4-yl)-4-(4-trifluoromethylphenyl)piperidin-4-yl]methylamine

The title compound was prepared using the methods described in Example14. LC-MS (LCT2) m/z 376 [M+H⁺], R_(t) 13.07 min.

¹H NMR (MeOD) δ 1.93-2.04 (2H, m), 2.40-2.46 (2H, m), 2.87 (2H, s),3.47-3.58 (2H, m), 4.36-4.43 (2H, m), 6.65 (1H, d, J=3.5 Hz), 7.13 (1H,d, J=3.5 Hz), 7.68-7.77 (4H, m), 8.13 (1H, s)

Example 33C-[1-(9H-Purin-6-yl)-4-(4-trifluoromethylphenyl)piperidin-4-yl]methylamine

The title compound was prepared using the methods described in Examples14 and 15. LC-MS (LCT2) m/z 377 [M+H⁺], R_(t) 4.19 min.

¹H NMR (MeOD) δ 1.92-2.03 (2H, m), 2.41-2.46 (2H, m), 2.87 (2H, s),3.62-3.71 (2H, m) 4.79-4.87 (2H, m), 7.69-7.78 (4H, m), 8.02 (1H, s),8.21 (1H, s)

Example 34C-[1-(7H-Pyrrolo[2,3-d]pyrimidin-4-yl)-4-(3-trifluoromethylphenyl)piperidin-4-yl]methylamine

The title compound was prepared using the methods described in Example14. LC-MS (LCT2) m/z 376 [M+H⁺], R_(t) 2.90 min.

¹H NMR (MeOD) δ 1.96-2.07 (2H, m), 2.40-2.45 (2H, m), 2.89 (2H, s),3.49-3.59 (2H, m), 4.33-4.42 (2H, m), 6.66 (1H, d, J=3.5 Hz), 7.14 (1H,d, J=3.5 Hz), 7.61-7.81 (4H, m), 8.14 (1H, s)

Example 35C-[1-(9H-Purin-6-yl)-4-(3-trifluoromethylphenyl)piperidin-4-yl]methylamine

The title compound was prepared using the methods described in Examples14 and 15. LC-MS (LCT2) m/z 377 [M+H⁺], R_(t) 3.97 min.

¹H NMR (MeOD) δ 1.94-2.05 (2H, m), 2.39-2.44 (2H, m), 2.89 (2H, s),3.65-3.73 (2H, m), 4.80-5.10 (2H, m), 7.51-7.81 (4H, m), 8.02 (1H, s),8.21 (1H, s)

Example 36C-[4-(3,4-Difluorophenyl)-1-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)piperidin-4-yl]methylamine

The title compound was prepared using the methods described in Example14. LC-MS (LCT2) m/z 344 [M+H⁺], R_(t) 2.42 min.

¹H NMR (MeOD) δ 1.88-1.99 (2H, m), 2.32-2.37 (2H, m), 2.84 (2H, s),3.45-3.57 (2H, m), 4.34-4.41 (2H, m), 6.64 (1H, d, J=3.5 Hz), 7.13 (1H,d, J=3.5 Hz), 7.31-7.47 (3H, m), 8.14 (1H, s)

Example 37C-[4-(3,4-Difluorophenyl)-1-(9H-purin-6-yl)piperidin-4-yl]methylamine

The title compound was prepared using the methods described in Examples14 and 15. LC-MS (LCT2) m/z 345 [M+H⁺], R_(t) 3.42 min.

¹H NMR (MeOD) δ 1.87-1.98 (2H, m), 2.31-2.36 (2H, m), 2.82 (2H, s),3.64-3.72 (2H, m), 4.79-4.95 (2H, m), 7.29-7.48 (3H, m), 8.02 (1H, s),8.21 (1H, s)

Example 38C-[4-(4-Methoxyphenyl)-1-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)piperidin-4-yl]methylamine

The title compound was prepared using the methods described in Example14. LC-MS (LCT2) m/z 338 [M+H⁺], R_(t) 2.37 min.

¹H NMR (MeOD) δ 1.82-1.93 (2H, m), 2.36-2.42 (2H, m), 2.81 (2H, s),3.41-3.51 (2H, m), 3.83 (3H, s), 4.38-4.45 (2H, m), 6.63 (1H, d, J=3.5Hz), 7.00-7.03 (2H, m), 7.12 (1H, d, J=3.5 Hz), 7.39-7.42 (2H, m), 8.13(1H, s)

Example 39C-[4-(4-Methoxyphenyl)-1-(9H-purin-6-yl)Piperidin-4-yl]methylamine

The title compound was prepared using the methods described in Examples14 and 15. LC-MS (LCT2) m/z 339 [M+H⁺], R_(t) 3.20 min.

¹H NMR (MeOD) δ 1.81-1.91 (2H, m), 2.37-2.42 (2H, m), 2.77 (2H, s),3.53-3.63 (2H, m), 3.84 (3H, s), 4.80-5.10 (2H, m), 7.02 (2H, d, J=9Hz), 7.41 (2H, d, J=9 Hz), 8.01 (1H, s), 8.20 (1H, s)

Example 40C-[4-(4-Benzyloxyphenyl)-1-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)piperidin-4-yl]methylamine

The title compound was prepared using the methods described in Example14. LC-MS (LCT2) m/z 414 [M+H⁺], R_(t) 3.87 min.

¹H NMR (MeOD) δ 1.84-1.89 (2H, m), 2.36-2.38 (2H, m), 2.78 (2H, s),3.44-3.49 (2H, m), 4.37-4.40 (2H, m), 5.11 (2H, s), 6.62-6.64 (1H, m),7.07-7.13 (3H, m), 7.30-7.46 (7H, m), 8.12 (1H, s)

Example 41C-[4-(4-Benzyloxyphenyl)-1-(9H-purin-6-yl)piperidin-4-yl]methylamine

The title compound was prepared using the methods described in Examples14 and 15. LC-MS (LCT2) m/z 415 [M+H⁺], R_(t) 4.85 min.

¹H NMR (MeOD) δ 1.81-1.91 (2H, m), 2.37-2.42 (2H, m), 2.73 (2H, s),3.54-3.63 (2H, m), 4.80-5.10 (2H, m), 5.13 (2H, s), 7.09 (2H, d, J=9Hz), 7.32-7.48 (7H, m), 8.01 (1H, s), 8.20 (1H, s)

Example 42[4-(4-Chloro-phenyl)-1-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-piperidin-4-ylmethyl]-methyl-amine

42A. Bis-(2-chloro-ethyl)-carbamic acid tert-butyl ester

A suspension of bis-(2-chloro-ethyl)-amine hydrochloride (5 g, 0.028mol) in dichloromethane (42 ml) was rapidly stirred with 10% aqueoussodium hydroxide (28 ml) in an ice bath, to which di-tert-butyldicarbonate (6.11 g, 0.028 mol) in dichloromethane (28 ml) was added.After stirring at room temperature for 18.5 hours, dichloromethane (30ml) was added to the reaction mixture and the two phases were separated.The aqueous phase was further extracted with dichloromethane (30 ml).The combined organic layers were dried (Mg₂SO₄), filtered andconcentrated to give bis-(2-chloro-ethyl)-carbamic acid tert-butyl ester(6.74 g, 0.028 mol, 100%). ¹H NMR (250 MHz, CDCl₃): 1.48 (9H, s),3.62-3.68 (8H, m).

42B. 4-(4-Chlorophenyl)-4-cyano-piperidine-1-carboxylic acid tert-butylester

Sodium hydride (60% dispersion in mineral oil, 2.9 g, 72.3 mmol) wasadded in small portions, over a period of 1 hour, to a solution ofbis-(2-chloro-ethyl)-carbamic acid tert-butyl ester (6.74 g, 28 mmol)and 4-chlorobenzyl cyanide (3.8 g, 25 mmol) in anhydrousdimethylformamide (25 ml). The reaction mixture was heated at 65° C. for1 hour and then stirred at room temperature for 89 hours. After thisperiod, the reaction mixture was poured into ice/water (60 ml) andextracted with ethyl acetate (2×100 ml). The combined organic layerswere washed with water and brine, dried, filtered and concentrated.Flash column chromatography on silica, eluting withhexane/dichloromethane/ethyl acetate (8:1:1), gave4-(4-chlorophenyl)-4-cyano-piperidine-1-carboxylic acid tert-butyl ester(5.6 g, 17.5 mmol, 70%) as a white solid. LC-MS (LCT) m/z 320 [M⁺],R_(t) 7.71 min.

42C. 4-(4-Chlorophenyl)-4-formyl-piperidine-1-carboxylic acid tert-butylester

A solution of 4-(4-chlorophenyl)-4-cyano-piperidine-1-carboxylic acidtert-butyl ester (2.0 g, 6.2 mmol,) in dry toluene (30 ml) at −78° C.,under nitrogen, was treated with a solution of DIBAL-H (10 ml, 10 mmol,1M solution in toluene). The reaction was maintained at −78° C. for 3hours, at which time it was quenched by slow addition a saturatedsolution of ammonium chloride (7.3 ml) and allowed to warm to roomtemperature. The reaction mixture was poured into water (50 ml) andextracted with ethyl acetate (2×100 ml). The organic layer wasseparated, dried (Mg₂SO₄), filtered and concentrated. Flash columnchromatography on silica, eluting with 20% ethyl acetate in hexane, gave4-(4-chlorophenyl)-4-formyl-piperidine-1-carboxylic acid tert-butylester (453 mg, 1.4 mmol, 22%) as a white solid. LC-MS (LCT2) m/z 346[M+Na⁺], R_(t) 8.49 min.

42D. 4-(4-Chloro-phenyl)-4-methylaminomethyl-piperidine-1-carboxylicacid tert-butyl ester

A mixture of methylamine in ethanol (18 ml, 33% in ethanol) and4-(4-chlorophenyl)-4-formyl-piperidine-1-carboxylic acid tert-butylester (206 mg, 0.62 mmol) was stirred at room temperature overnight. Thesolvents were concentrated. The crude material was redissolved inmethanol (18 ml) followed by addition of sodium borohydride (49 mg, 1.29mmol). After stirring for 40 minutes at room temperature, the mixturewas partitioned between ethyl acetate (100 ml) and a saturated aqueoussolution of sodium hydrogen carbonate (100 ml). After separation of thetwo phases the aqueous phase was re-extracted with ethyl acetate (100ml). The combined organic layers were dried (Na₂SO₄), filtered andconcentrated. Flash column chromatography on silica, eluting with 10%methanol in dichloromethane gave4-(4-chloro-phenyl)-4-methylaminomethyl-piperidine-1-carboxylic acidtert-butyl ester (142 mg, 0.42 mmol, 68%). GC-MS m/z 239 [(M-Boc)⁺],R_(t) 5.18 min. ¹H NMR (250 MHz, CDCl₃): 1.43 (9H, s), 1.80-1.88 (2, m),2.15-2.24 (2, m), 2.31 (3H, s), 2.81 (2H, s), 2.98-3.09 (2H, m),3.72-3.78 (2H, m), 7.32 (2H, d, 9 Hz), 7.38 (2H, d, 9 Hz).

42E. [4-(4-Chlorophenyl)-piperidin-4-ylmethyl]-methylaminebishydrochloride

A 4M solution of hydrochloric acid in dioxane (10 ml) was added dropwiseto a solution of4-(4-chlorophenyl)-4-methylaminomethyl-piperidine-1-carboxylic acidtert-butyl ester (142 mg, 0.42 mmol) in methanol (10 ml). The reactionwas stirred overnight at room temperature. After this period of time,the solvents were concentrated to give[4-(4-chlorophenyl)-piperidin-4-ylmethyl]-methylamine bis-hydrochloride(132 mg, 0.42 mmol, 100%). This compound was used in the subsequent stepwithout further purification. LC-MS (LCT2) m/z 239 [M+H⁺], R_(t) 0.53min.

42F.[4-(4-Chlorophenyl)-1-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-piperidin-4-ylmethyl]-methylamine

A solution of 4-chloro-7H-pyrrolo[2,3-d]pyrimidine (15.5 mg, 0.1 mmol),[4-(4-chlorophenyl)-piperidin-4-ylmethyl]-methylamine bis-hydrochloride(34 mg, 0.11 mmol) and triethylamine (150 μL, 0.7 mmol) in n-butanol (1ml) was heated at 100° C. in a microwave reactor for 60 minutes. Aftercooling the reaction the solvents were concentrated. Purification onSCX-II acid resin, eluting with methanol then 2M ammonia/methanol,followed by further purification by flash column chromatography onsilica, eluting with 15% methanol in dichloromethane, gave[4-(4-chlorophenyl)-1-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-piperidin-4-ylmethyl]-methylamine(12.3 mg, 0.034 mmol, 34%). LC-MS (LCT2) m/z 356 [M+H⁺], R_(t) 2.64 min.

¹H NMR (MeOD) δ 1.94-2.05 (2H, m), 2.28 (3H, s), 2.36-2.41 (2H, m), 2.80(2H, s), 3.50-3.61 (2H, m), 4.30-4.39 (2H, m), 6.65 (1H, d, J=4 Hz),7.14 (1H, d, J=4 Hz), 7.42-7.52 (4H, m), 8.13 (1H, s)

Example 43[4-(4-Chlorophenyl)-1-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-piperidin-4-ylmethyl]-isopropylamine

The title compound was prepared by the method described in Example 42,but replacing methylamine with isopropylamine in step 44D. LC-MS (LCT2)m/z 384 [M+H⁺], R_(t) 2.80 min.

¹H NMR (MeOD) δ 0.97 (6H, d, J=8 Hz), 1.96-2.07 (2H, m), 2.35-2.41 (2H,m), 2.61 (1H, septet, J=8 Hz), 2.83 (2H, s), 3.52-3.62 (2H, s),4.31-4.37 (2H, m), 6.65 (1H, d, J=4 Hz), 7.14 (1H, d, J=4 Hz), 7.43 (2H,d, J=8 Hz), 7.52 (2H, d, J=8 Hz), 8.13 (1H, s)

Example 44[4-(4-Chlorobenzyl)-1-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-piperidin-4-yl]-dimethylamine

44A.[4-(4-Chlorobenzyl)-1-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-piperidin-4-yl]-dimethylamine

A mixture of4-(4-chlorobenzyl)-1-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-piperidin-4-ylaminefrom Example 17 (20 mg, 0.06 mmol), formic acid (0.16 ml, 96%) andformaldehyde (4 μl, 0.05 mmol, 37% in water) was heated at 100° C. for48 hours. After cooling the reaction mixture to room temperature, themixture was basified to pH 10 by addition of a 1M aqueous solution ofsodium hydroxide, followed by extraction with ethyl acetate (20 ml). Theorganic layer was dried (Mg₂SO₄), filtered and concentrated. Flashcolumn chromatography on silica, eluting with 15% methanol indichloromethane gave[4-(4-chlorobenzyl)-1-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-piperidin-4-yl]-dimethylamine(3.8 mg, 0.01 mmol, 17%). LC-MS (LCT2) m/z 370 [M+H⁺], R_(t) 2.62 min.

¹H NMR (MeOD) δ 1.42-1.53 (2H, m), 2.02-2.18 (2H, m), 2.43 (6H, s), 2.81(2H, s), 3.51-3.61 (2H, m), 4.30-4.35 (2H, m), 6.60 (1H, d, J=4 Hz),7.09 (1H, d, J=4 Hz), 7.17-7.28 (4H, m), 8.06 (1H, s)

Example 45C-[4-(3,4-Dichlorobenzyl)-1-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)piperidin-4-yl]methylamine

The title compound was prepared using the methods described in Example19. LC-MS (LCT2) m/z 390 [M+H⁺], R_(t) 3.37 min.

¹H NMR (MeOD) δ 1.48-1.64 (4H, m), 2.63 (2H, s), 2.81 (2H, s), 3.85-4.16(4H, m), 6.64 (1H, d, J=3.5 Hz), 7.12-7.21 (2H, m), 7.44-7.47 (2H, m),8.13 (1H, s)

Example 46 C-[4-(3,4-Dichlorobenzyl)-1-(9H-purin-6-yl)piperidin-4-yl]methylamine

The title compound was prepared using the methods described in Examples19 and 23. LC-MS (LCT2) m/z 391 [M+H⁺], R_(t) 4.42 min.

¹H NMR (MeOD) δ 1.40-1.53 (4H, m), 2.51 (2H, s), 2.69 (2H, s), 4.00-4.11(2H, m), 4.30-4.40 (2H, m), 7.03-7.08 (1H, m), 7.30-7.35 (2H, m), 7.88(1H, s), 8.08 (1H, s)

Example 47

C-[1-(7H-Pyrrolo[2,3-d]pyrimidin-4-yl)-4-(4-trifluoromethoxybenzyl)piperidin-4-yl]methylamine

The title compound was prepared using the methods described in Example19. LC-MS (LCT2) m/z 406 [M+H⁺], R_(t) 3.39 min.

¹H NMR (MeOD) δ 1.61-1.65 (4H, m), 2.63 (2H, s), 2.86 (2H, s), 3.89-4.15(4H, m), 6.64 (1H, d, J=4 Hz), 7.13 (1H, d, J=4 Hz), 7.21-7.37 (4H, m),8.13 (1H, s)

Example 48C-[1-(9H-Purin-6-yl)-4-(4-trifluoromethoxybenzyl)piperidin-4-yl]methylamine

The title compound was prepared using the methods described in Examples19 and 23. LC-MS (LCT2) m/z 407 [M+H⁺], R_(t) 4.42 min.

¹H NMR (MeOD) δ 1.54-1.63 (4H, m), 2.64 (2H, s), 2.86 (2H, s), 4.18-4.28(2H, m), 4.40-4.50 (2H, m), 7.20-7.36 (4H, m), 8.01 (1H, s), 8.21 (1H,s)

Example 494-(3,4-Dichlorobenzl)-1-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)piperidin-4-ylamine

The title compound was prepared using the methods described in Example17. LC-MS (LCT) m/z 376 [M+H⁺], R_(t) 3.30 min.

¹H NMR (MeOD) δ 1.54-1.61 (2H, m), 1.72-1.83 (2H, m), 2.79 (2H, s),3.73-3.84 (2H, m), 4.28-4.37 (2H, m), 6.64 (1H, d, J=3.5 Hz), 7.13 (1H,d, J=3.5 Hz), 7.18-7.22 (1H, m), 7.46-7.54 (2H, m), 8.14 (1H, s)

Example 50 4-(3,4-Dichlorobenzyl)-1-(9H-purin-6-yl)piperidin-4-yl amine

The title compound was prepared using the methods described in Examples17 and 18. LC-MS (LCT) m/z 377 [M+H⁺], R_(t) 4.19 min.

¹H NMR (MeOD) δ 1.37-1.46 (2H, m), 1.58-1.69 (2H, m), 2.67 (2H, s),3.76-3.85 (2H, m), 4.65-4.75 (2H, m), 7.05-7.09 (1H, m), 7.32-7.36 (2H,m), 7.88 (1H, s), 8.08 (1H, s)

Example 511-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-4-(4-trifluoromethoxybenzyl)piperidin-4-ylamine

The title compound was prepared using the methods described in Example17. LC-MS (LCT) m/z 392 [M+H⁺], R_(t) 3.34 min.

¹H NMR (MeOD) δ 1.56-1.61 (2H, m), 1.74-1.85 (2H, m), 2.85 (2H, s),3.76-3.87 (2H, m), 4.26-4.35 (2H, m), 6.64 (1H, d, J=3.5 Hz), 7.13 (1H,d, J=3.5 Hz), 7.23-7.39 (4H, m), 8.14 (1H, s)

Example 521-(9H-Purin-6-yl)-4-(4-trifluoromethoxybenzyl)piperidin-4-ylamine

The title compound was prepared using the methods described in Examples17 and 18. LC-MS (LCT) m/z 393 [M+H⁺], R_(t) 4.20 min.

¹H NMR (MeOD) δ 1.55-1.60 (2H, m), 1.72-1.92 (2H, m), 2.85 (2H, s),3.92-4.02 (2H, m), 4.76-4.88 (2H, m), 7.23-7.38 (4H, m), 8.01 (1H, s),8.21 (1H, s)

Example 531-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-4-(3-chlorobenzyl)piperidin-4-ylamine

53A.4-(3-chlorobenzyl)-4-(2-methylpropane-2-sulphinylamino)-piperidine-1-carboxylicacid tert-butyl ester

A solution of N-BOC-piperidone (0.205 g, 1.03 mmol), t-butylsulphinamide(0.13 g, 1.07 mmol) and titanium tetraethoxide (0.42 ml, 2.0 mmol) indry THF (5 ml) was refluxed under nitrogen for 5 h. The cooled solutionwas diluted with brine (10 ml) and ethyl acetate (10 ml). The suspensionwas shaken, the filtered through Celite, washing with ethyl acetate (10ml). The two-phase filtrate was separated and the organic layer wasdried (Na₂SO₄) filtered and concentrated to give the crude sulphinimine(0.293 g). The crude sulphinimine (0.293 g) was suspended in dry THF (2ml) and stirred at room temperature under nitrogen. A solution of3-chlorobenzyl magnesium bromide (ca. 4 mmol) (freshly prepared as asolution in diethyl ether from 3-chlorobenzylbromide and magnesiumturnings) was added to give an orange solution. After 3 hours, themixture was diluted with saturated aqueous ammonium chloride (20 ml) andextracted with ethyl acetate (20 ml). The extract was washed with water(20 ml), brine (10 ml), dried (Na₂SO₄), filtered and concentrated. Flashcolumn chromatography, eluting with 50% ethyl acetate-hexanes, gave4-(3-chlorobenzyl)-4-(2-methylpropane-2-sulphinylamino)-piperidine-1-carboxylicacid tert-butyl ester as a straw-coloured foam (0.139 g, 0.324 mmol,31%). LC-MS (LCT) m/z 451, 453 [M+Na⁺], R_(t) 8.22 min.

53B.1-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-4-(3-chlorobenzyl)piperidin-4-ylamine

A solution of4-(3-chlorobenzyl)-4-(2-methylpropane-2-sulpinylamino)-piperidine-1-carboxylicacid tert-butyl ester (0.134 g, 0.312 mmol) and 4M HCl in dioxane (2 ml,8 mmol) in dry methanol (2 ml) was stirred at room temperature for 5hours. The mixture was concentrated then applied to an acidic resincartridge (SCX-II, 5 g) and eluted with methanol and 2Mammonia-methanol. The amine-containing fractions were further purifiedby application to a basic resin cartridge (NH2, 2 g), eluting withmethanol, to give the crude amine as a yellow oil (0.063 g). A solutionof the crude amine (0.063 g), triethyl amine (0.3 ml, 2 mmol) and4-4-chloro-7H-pyrrolo[2,3-d]pyrimidine (0.039 g, 0.25 mmol) in dry1-butanol (1 ml) was refluxed under nitrogen for 16 hours. The solutionwas concentrated and applied to an acidic resin column (SCX, 2 g) theneluted with methanol and 1M ammonia-methanol. The basic fractions werecombined and concentrated. Flash silica column chromatography, elutingwith 10% methanol-dichloromethane, gave the product as a yellow oil.Trituration and washing with diethyl ether gave a cream solid (0.031 g,0.0907 mmol, 29%). LC-MS (LCT) m/z 344, 342 [M+H⁺], R_(t) 2.90 min.

¹H NMR (MeOD) δ 1.45 (2H, d, J=13 Hz), 1.63-1.68 (2H, m), 2.69 (2H, s),3.65-3.69 (2H, m), 4.19 (2H, d, J=14 Hz), 6.52 (1H, d, 4 Hz), 7.01 (1H,d, J=4 Hz), 7.08 (1H, d, J=7 Hz), 7.15-7.21 (3H, m), 8.01 (1H, s)

Example 544-(4-Chlorobenzyl)-1-(1H-pyrrolo[2,3-b]pyridin-4-yl)-piperidin-4-ylamine

The title compound was prepared in a similar manner to Examples 14 and17, using 4-fluoro-1-triisopropylsilanyl-1H-pyrrolo[2,3-b]pyridine (OrgLett 2003, 5, 5023-5026) in place of4-chloro-7H-pyrrolo[2,3-d]pyrimidine, with NMP as solvent and microwaveheating at 160° C. LC-MS (LCT2) m/z 341, 343 [M+H⁺], R_(t) 2.39 min.

¹H NMR (CDCl₃) δ 0.98-1.47 (2H, m), 1.76-1.80 (2H, m), 2.65 (2H, s),3.43-3.48 (2H, m), 3.78-3.81 (2H, m), 6.37 (1H, d, J=6 Hz), 6.46 (1H, d,J=4 Hz), 7.05-7.07 (3H, m), 7.23-7.25 (2H, m), 7.86 (1H, d, J=6 Hz)

Example 554-(2-Chlorobenzyl)-1-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)piperidin-4-ylamine

The title compound was prepared as described in Example 53. LC-MS (LCT2)m/z 342 [M+H⁺], R_(t) 2.86 min.

¹H NMR (MeOD) δ 1.61-1.63 (2H, m), 1.82-1.87 (2H, m), 3.01 (2H, s),3.68-3.73 (2H, m), 4.37-4.40 (2H, m), 6.60-6.62 (1H, m), 7.11-7.12 (1H,m), 7.23-7.29 (2H, m), 7.37-7.43 (2H, m), 8.11 (1H, s)

Example 564-(4-tert-Butylbenzyl)-1-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)piperidin-4-ylamine

The title compound was prepared as described in Example 53. LC-MS (LCT2)m/z 364 [M+H⁺], R_(t) 4.24 min.

¹H NMR (MeOD) δ 1.32 (9H, s), 1.55-1.58 (2H, m), 1.75-1.81 (2H, m), 2.78(2H, s), 3.79-3.85 (2H, m), 4.24-4.29 (2H, m), 6.63 (1H, d, J=4 Hz),7.13 (1H, d, J=4 Hz), 7.37 (2H, d, J=8 Hz), 7.37 (2H, d, J=8 Hz), 8.12(1H, s)

Example 574-(3-Methoxybenzyl)-1-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)piperidin-4-ylamine

The title compound was prepared as described in Example 53. LC-MS (LCT2)m/z 338 [M+H⁺], R_(t) 2.61 min.

¹H NMR (MeOD) δ 1.53-1.55 (2H, m), 1.72-1.77 (2H, m), 2.73 (2H, s),3.75-3.79 (2H, m), 3.78 (3H, s), 4.23-4.26 (2H, m), 6.58-6.59 (1H, m),6.80-6.82 (3H, m), 7.09-7.10 (1H, m), 7.20-7.21 (1H, m), 8.12 (1H, s)

Example 58 4-(3-Trifluoromethoxybenzyl)-1-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)piperidin-4-ylamine

The title compound was prepared as described in Example 53. LC-MS (LCT2)m/z 392 [M+H⁺], R_(t) 3.47 min.

¹H NMR (MeOD) δ 1.40-1.43 (2H, m), 1.59-1.65 (2H, m), 2.68 (2H, s),3.60-3.64 (2H, m), 4.16-4.18 (2H, m), 6.47 (1H, d, J=3.5 Hz), 6.98 (1H,d, J=3.5 Hz), 7.03-7.12 (2H, m), 7.26-7.29 (1H, m), 8.01 (1H, s)

Example 594-(2,4-Dichlorobenzyl)-1-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)piperidin-4-ylamine

The title compound was prepared as described in Example 53. LC-MS (LCT2)m/z 376 [M+H⁺], R_(t) 3.53 min.

¹H NMR (MeOD) δ 1.59-1.62 (2H, m), 1.79-1.84 (2H, m), 2.98 (2H, s),3.67-3.72 (2H, m), 4.38-4.41 (2H, m), 6.62-6.63 (1H, m), 7.11-7.13 (1H,m), 7.30-7.48 (3H, m), 8.11 (1H, s)

Example 604-(2-Chloro-4-fluorobenzyl)-1-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)piperidin-4-ylamine

The title compound was prepared as described in Example 53. LC-MS (LCT2)m/z 360 [M+H⁺], R_(t) 2.98 min.

¹H NMR (MeOD) δ 1.56-1.59 (2H, m), 1.76-1.81 (2H, m), 2.92 (2H, s),3.64-3.68 (2H, m), 4.36-4.38 (2H, m), 6.58-6.59 (1H, m), 7.01-7.05 (1H,m), 7.09-7.10 (1H, m), 7.19-7.21 (1H, m), 7.35-7.38 (1H, m), 8.11 (1H,s)

Example 614-(2,6-Dichlorobenzyl)-1-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)piperidin-4-ylamine

The title compound was prepared as described in Example 53. LC-MS (LCT2)m/z 376 [M+H⁺], R_(t) 3.11 min.

¹H NMR (MeOD) δ 1.70-1.73 (2H, m), 1.86-1.90 (2H, m), 3.24 (2H, s),3.59-3.64 (2H, m), 4.41-4.44 (2H, m), 6.58-6.59 (1H, m), 7.08-7.09 (1H,m), 7.17-7.20 (1H, m), 7.38-7.40 (2H, m), 8.09 (1H, s)

Example 62[4-(4-Chlorobenzyl)-1-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)piperidin-4-yl]methylamine

62A4-(4-Chlorobenzyl)-4-(2-methylpropane-2-sulfinylamino)piperidine-1-carboxylicacid tert-butyl ester

The title compound was prepared as described in Example 53. LC-MS (LCT2)m/z 451 [M+Na⁺], R_(t) 8.39 min.

62B4-(4-Chlorobenzyl)-4-[methyl(2-methylpropane-2-sulfinyl)amino]piperidine-1-carboxylicacid tert-butyl ester

To a solution of4-(4-chlorobenzyl)-4-(2-methylpropane-2-sulfinylamino)-piperidine-1-carboxylicacid tert-butyl ester (205 mg, 0.478 mmol) in DMF (4.8 mL) at 0° C. wasadded sodium hydride (25 mg of a 60% dispersion in mineral oil, 0.621mmol). After 15 min methyl iodide (33 □l, 0.526 mmol) was added, and thesolution warmed to rt. After 12 h, sodium hydride (120 mg, 60%dispersion in mineral oil, 3.00 mmol) and methyl iodide (165 □l, 2.65mmol) were added. After 30 min water (20 mL) was added and the solutionextracted with ethyl acetate (3×20 mL). Organic extracts were combined,dried over magnesium sulphate and the resulting crude product waspurified by silica column chromatography, eluting with 66% ethylacetate-hexanes, to give the title product as an oil (163 mg, 77%).LC-MS (LCT2) m/z 465 [M+Na⁺], R_(t) 8.41 min.

62C [4-(4-Chlorobenzyl)piperidin-4-yl]methylamine

The title compound was prepared as described in Example 53 by treatmentof the product of 62B with HCl. LC-MS (LCT2) m/z 239 [M+H⁺], R_(t) 0.59min.

62D[4-(4-Chlorobenzyl)-1-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)piperidin-4-yl]methylamine

The title compound was prepared as described in Example 53. LC-MS (LCT2)m/z 356 [M+H⁺], R_(t) 2.72 min.

¹H NMR (MeOD) δ 1.62-1.65 (4H, m), 2.44 (3H, s), 2.82 (2H, s), 3.74-3.78(2H, m), 4.21-4.34 (2H, m), 6.61-6.62 (1H, m), 7.10-7.12 (1H, m),7.17-7.19 (2H, m), 7.30-7.32 (2H, m), 8.12 (1H, s)

Example 631-(7H-Pvrrolo[2,3-d]pyrimidin-4-yl)-4-(2trifluoromethoxybenzyl)piperidin-4-ylamine

The title compound was prepared as described in Example 53. LC-MS (LCT2)m/z 392 [M+H⁺], R_(t) 3.31 min.

¹H NMR (MeOD) δ 1.57-1.59 (2H, m), 1.74-1.78 (2H, m), 2.90 (2H, s),3.73-3.78 (2H, m), 4.30-4.34 (2H, m), 6.59-6.61 (1H, m), 7.11-7.13 (1H,m), 7.33-7.44 (4H, m), 8.12 (1H, s)

Example 644-(2,5-Dichlorobenzyl)-1-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)piperidin-4-ylamine

The title compound was prepared as described in Example 53. LC-MS (LCT2)m/z 376 [M+H⁺], R_(t) 3.34 min.

¹H NMR (MeOD) δ 1.59-1.61 (2H, m), 1.79-1.84 (2H, m), 3.04 (2H, s),3.64-3.69 (2H, m), 4.38-4.41 (2H, m), 6.59-6.60 (1H, m), 7.10-7.12 (1H,m), 7.21-7.25 (1H, m), 7.30-7.32 (1H, m), 7.41-7.43 (1H, m), 8.12 (1H,s)

Example 654-(2,3-Dichlorobenzyl)-1-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)piperidin-4-ylamine

The title compound was prepared as described in Example 53. LC-MS (LCT2)m/z 376 [M+H⁺], R_(t) 3.16 min.

¹H NMR (MeOD) δ 1.58-1.61 (2H, m), 1.79-1.84 (2H, m), 2.95 (2H, s),3.64-3.69 (2H, m), 4.38-4.41 (2H, m), 6.59-6.60 (1H, m), 7.10-7.11 (1H,m), 7.21-7.25 (1H, m), 7.36-7.43 (2H, m), 8.11 (1H, s)

Example 664-(4-tert-Butylbenzyl)-1-(1H-pyrrolo[2,3-b]pyridin-4-yl)-piperidin-4-ylamine

The title compound was prepared in a similar manner to Example 54. LC-MS(LCT2) m/z 363 [M+H⁺], R_(t) 3.19 min.

¹H NMR (MeOD) δ 1.33 (9H, s), 1.60-1.65 (2H, m), 1.85-1.92 (2H, m), 2.81(2H, s), 3.48-3.52 (2H, m), 3.70-3.78 (2H, s), 6.52-6.52 (2H, m),7.17-7.21 (3H, m), 7.38-7.40 (2H, m), 7.90-7.91 (1H, m)

Example 674-(2,4-Dichlorobenzyl)-1-(1H-pyrrolo[2,3-b]pyridin-4-yl)-piperidin-4-ylamine

The title compound was prepared in a similar manner to Example 54. LC-MS(LCT2) m/z 375, 377, 379 [M+H⁺], R_(t) 2.80 min.

¹H NMR (MeOD)

1.52-1.55 (2H, m), 1.81-1.86 (2H, m), 2.90 (2H, s), 3.31-3.35 (2H, m),3.68-3.70 (2H, m), 6.38-6.39 (2H, m), 7.06 (1H, d, J=4), 7.21 (1H, dd,J=8, 2 Hz), 7.29 (1H, d, J=8 Hz), 7.38 (1H, d, J=2), 7.80 (1H, d, J=6Hz)

Example 68C-[4-(4-Chlorophenyl)-1-(1H-pyrrolo[2,3-b]pyridin-4-yl)-piperidin-4-yl]-methylamine

68A. 4-Chloro-1H-pyrrolo[2,3-b]pyridine-5-carboxylic acid ethyl ester

To a solution of4-chloro-1-(4-methoxybenzyl)-1H-pyrrolo[2,3-b]pyridine-5-carboxylic acidethyl ester (prepared as described in J. Heterocycl. Chem. 1972, 235 andBioorg. Med. Chem. Lett. 2003, 2405) (3.48 g, 10 mmol) in TFA (20 mL),conc. H₂SO₄ (1.5 mL) and anisole (3 mL) were added at room temperature.The resulting solution was stirred at this temperature for 3 hours andthen basified slowly by addition of ice-cold aqueous NaHCO₃. The aqueoussolution was extracted with ethyl acetate and the combined organiclayers were dried (Na₂SO₄) and concentrated. The residue was filteredand washed with n-hexanes to give a yellow solid (1.04 g, 46%). LC-MS(LCT2) m/z 226 [M+H⁺], R_(t) 6.22 min.

68B4-[4-(4-Chlorophenyl)-4-(1,3-dioxo-1,3-dihydroisoindol-2-ylmethyl)-piperidin-1-yl]-1H-pyrrolo[2,3-b]pyridine-5-carboxylicacid ethyl ester

A mixture of 4-chloro-1H-pyrrolo[2,3-b]pyridine-5-carboxylic acid ethylester (34 mg, 0.15 mmol), and2-[4-(4-chlorophenyl)-piperidin-4-ylmethyl]-isoindole-1,3-dione(prepared by treatment ofC-[4-(4-chlorophenyl)piperidin-4-yl]methylamine hydrochloride, Example14, Step C with phthalic anhydride in acetic acid at 120° C.) (54 mg,0.15 mmol) and triethylamine (0.1 mL) in n-butanol (2 mL) was irradiatedin a microwave reactor (300 W) for 1 hr at 120° C. with simultaneousair-cooling. The resulting solids were broken up, washed with methanol,filtered and dried to give a cream-coloured solid (49 mg, 60%). LC-MS(LCT2) m/z 544 [M+H⁺], R_(t) 7.83 min.

68C.4-[4-(4-Chlorophenyl)-4-(1,3-dioxo-1,3-dihydroisoindol-2-ylmethyl)-piperidin-1-yl]-1H-pyrrolo[2,3-b]pyridine-5-carboxylicacid

4-[4-(4-Chlorophenyl)-4-(1,3-dioxo-1,3-dihydroisoindol-2-ylmethyl)-piperidin-1-yl]-1H-pyrrolo[2,3-b]pyridine-5-carboxylicacid ethyl ester (49 mg, 0.09 mmol) was hydrolysed in a mixture of 2MNaOH (1 mL) and 1,4-dioxane (1 mL) at 80° C. overnight. The solution wasacidified by dropwise addition of conc. HCl. Solvents were evaporatedand the resulting solid was filtered and washed with water, then dried.A white solid (45 mg) was obtained which was used in the next stepwithout further purification.

68D.C-[4-(4-Chloro-phenyl)-1-(1H-pyrrolo[2,3-b]pyridin-4-yl)-piperidin-4-yl]-methylamine

A mixture of crude4-[4-(4-chlorophenyl)-4-(1,3-dioxo-1,3-dihydroisoindol-2-ylmethyl)-piperidin-1-yl]-1H-pyrrolo[2,3-b]pyridine-5-carboxylicacid (12.8 mg, 0.025 mmol) and water (1 mL) was irradiated in amicrowave reactor (250 W) for 2 hrs at 180° C. The resulting suspensionwas filtered and the filtrate was concentrated. Preparative TLC gave theproduct (4 mg, 47%). LC-MS (LCT2) m/z 342 [M+H⁺], R_(t) 2.19 min.

¹H NMR (MeOD) δ 2.00 (2H, m), 2.42 (2H, m), 2.85 (2H, s), 3.40 (2H, m),4.00 (2H, m), 6.45 (1H, d, J=5.8 Hz), 7.50 (4H, m), 8.06 (1H, d, J=5.8Hz), 8.2 (1H, s)

Example 694-Amino-1-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-piperidine-4-carboxylic acid4-chloro-benzylamide

69A.4-tert-Butoxycarbonylamino-4-(4-chloro-benzylcarbamoyl)-piperidine-1-carboxylicacid tert-butyl ester

Dry DMF (1 mL) was added to a mixture of4-tert-butoxycarbonylamino-piperidine-1,4-dicarboxylic acid monotert-butyl ester (151 mg, 0.44 mmol) and HATU (220 mg, 0.58 mmol) undernitrogen. N-Ethyldiisopropylamine (0.38 mL, 2.1 mmol) was added to thesolution and the reaction mixture was stirred for 15 min.4-Chlorobenzylamine (70 uL, 0.57 mmol) was added and the solution wasstirred for 23 h at rt and under nitrogen. The reaction mixture waspartioned between dichloromethane (10 mL) and water (10 mL). The aqueousphase was further extracted with dichloromethane (20 mL). The combinedorganic layers were dried (Mg₂SO₄), filtered and concentrated. Flashcolumn chromatography on silica, eluting with 4% methanol indichloromethane, gave4-tert-butoxycarbonylamino-4-(4-chloro-benzylcarbamoyl)-piperidine-1-carboxylicacid tert-butyl ester (177 mg, 0.38 mmol, 86%). LC-MS (LCT2) m/z 490[M+Na⁺], R_(t) 8.09 min.

69B. 4-Amino-piperidine-4-carboxylic acid 4-chloro-benzylamidedihydrochloride

A 4M solution of HCl in dioxane (7.7 ml, 31 mmol) was added dropwise toa solution of4-tert-butoxycarbonylamino-4-(4-chloro-benzylcarbamoyl)-piperidine-1-carboxylicacid tert-butyl ester (96 mg, 0.20 mmol) in methanol (7.7 mL) andstirred at rt for 17 h. The solvents were concentrated to give4-amino-piperidine-4-carboxylic acid 4-chloro-benzylamidedihydrochloride (71 mg, 0.20 mmol, 100%) that was used in the next stepwithout further purification.

¹H NMR (500 MHz, CD₃OD): 2.18 (2H, m), 2.64 (2H, m), 3.44 (4H, m), 4.47(2H, s), 7.36 (4H, m).

69C. 4-Amino-1-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-piperidine-4-carboxylicacid 4-chloro-benzylamide

A degassed mixture of 4-amino-piperidine-4-carboxylic acid4-chloro-benzylamide dihydrochloride (48 mg, 0.13 mmol),4-chloro-7H-pyrrolo[2,3-d]pyrimidine (21 mg, 0.12 mmol), triethylamine(126 uL, 0.9 mmol) and n-butanol (1.2 mL) was stirred at 100° C. for 18h. The solvents were removed by evaporation and the crude mixture wasfirst purified on a SCX-II acid resin, eluting with methanol then 2Mammonia/methanol, and then by preparative TLC, eluting with 10% methanolin dichloromethane, to give4-amino-1-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-piperidine-4-carboxylic acid4-chloro-benzylamide (37 mg, 0.096 mmol, 80%). LC-MS (LCT2) m/z 385[M+H⁺], R_(t) 2.84 min.

¹H NMR (MeOD) δ 1.60-1.62 (2H, m), 2.19-2.25 (2H, m), 3.65-3.71 (2H, m),4.38 (2H, s), 4.47-4.50 (2H, m), 6.65 (1H, d, J=4 Hz), 7.14 (1H, d, J=4Hz), 7.27-7.33 (4H, m), 8.14 (1H, s)

Example 704-Amino-1-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-piperidine-4-carboxylic acid3-chloro-benzylamide

The title compound was prepared as described for Example 69. LC-MS(LCT2) m/z 385 [M+H⁺], R_(t) 2.94 min.

¹H NMR (MeOD) δ 1.60-1.63 (2H, m), 2.20-2.25 (2H, m), 3.65-3.71 (2H, m),4.39 (2H, s), 4.48-4.51 (2H, m), 6.65 (1H, d, J=4 Hz), 7.14 (1H, d, J=4Hz), 7.22-7.32 (4H, m), 8.14 (1H, s)

Example 714-Amino-1-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-piperidine-4-carboxylic acid4-trifluoromethyl-benzylamide

The title compound was prepared as described for Example 69. LC-MS(LCT2) m/z 419 [M+H⁺], R_(t) 3.26 min.

¹H NMR (MeOD) δ 1.62-1.64 (2H, m), 2.20-2.26 (2H, m), 3.65-3.71 (2H, m),4.48-4.51 (4H, m), 6.65 (1H, d, J=4 Hz), 7.14 (1H, d, J=4 Hz), 7.49 (2H,d, J=8 Hz), 7.63 (2H, d, J=8 Hz), 8.14 (1H, s)

Example 724-Amino-1-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-piperidine-4-carboxylic acid4-fluoro-benzylamide

The title compound was prepared as described for Example 69. LC-MS(LCT2) m/z 369 [M+H⁺], R_(t) 2.43 min.

¹H NMR (MeOD) δ 1.59-1.62 (2H, m), 2.19-2.25 (2H, m), 3.65-3.70 (2H, m),4.38 (2H, s), 4.47-4.50 (2H, m), 6.65 (1H, d, J=4 Hz), 7.05 (2H, dd,J=8.5 Hz), 7.14 (1H, d, J=4 Hz), 7.30-7.33 (2H, m), 8.14 (1H, s)

Example 734-Amino-1-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-piperidine-4-carboxylic acid2-chloro-benzylamide

The title compound was prepared as described for Example 69. LC-MS(LCT2) m/z 385 [M+H⁺], R_(t) 2.77 min.

¹H NMR (MeOD) δ 1.61-1.64 (2H, m), 2.21-2.26 (2H, m), 3.66-3.71 (2H, m),4.49-4.50 (4H, m), 6.65 (1H, d, J=4 Hz), 7.14 (1H, d, J=4 Hz), 7.27-7.41(4H, m), 8.14 (1H, s)

Example 744-Amino-1-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-piperidine-4-carboxylic acid4-trifluoromethoxy-benzylamide

The title compound was prepared as described for Example 69. LC-MS(LCT2) m/z 435 [M+H⁺], R_(t) 3.55 min.

¹H NMR (MeOD) δ 1.61-1.63 (2H, m), 2.20-2.25 (2H, m), 3.66-3.71 (2H, m),4.42 (2H, s), 4.48-4.51 (2H, m), 6.65 (1H, d, J=4 Hz), 7.14 (1H, d, J=4Hz), 7.24 (2H, d, J=7 Hz), 7.40 (2H, d, J=7 Hz), 8.14 (1H, s)

Example 754-Amino-1-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-piperidine-4-carboxylic acid(4-chloro-benzyl)-methyl-amide

The title compound was prepared as described for Example 69. LC-MS(LCT2) m/z 399 [M+H⁺], R_(t) 3.13 min.

¹H NMR (MeOD) δ 1.76-1.78 (2H, m), 2.33-2.37 (2H, m), 3.18 (3H, br s),4.02-4.11 (4H, m), 4.95 (2H, s), 6.62-6.64 (1H, m), 7.10-7.13 (1H, m),7.22-7.26 (2H, m), 7.32-7.36 (2H, m), 8.13 (1H, s)

Example 764-Amino-1-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-piperidine-4-carboxylic acid4-tert-butyl-benzylamide

The title compound was prepared as described for Example 69. LC-MS(LCT2) m/z 407 [M+H⁺], R_(t) 4.28 min.

¹H NMR (MeOD) δ 1.31 (9H, s), 1.56-1.63 (2H, m), 2.18-2.25 (2H, m),3.60-3.70 (2H, m), 4.37 (2H, s), 4.40-4.50 (2H, m), 6.65 (1H, d, J=4Hz), 7.14 (1H, d, J=4 Hz), 7.24 (2H, d, J=8 Hz), 7.36 (2H, d, J=8 Hz),8.14 (1H, s)

Example 774-Amino-1-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-piperidine-4-carboxylic acid2,4-dichloro-benzylamide

The title compound was prepared as described for Example 69. LC-MS(LCT2) m/z 419 [M+H⁺], R_(t) 3.69 min.

¹H NMR (MeOD) δ 1.62-1.64 (2H, m), 2.17-2.25 (2H, m), 3.65-3.71 (2H, m),4.47-4.51 (4H, m), 6.65 (1H, d, J=4 Hz), 7.14 (1H, d, J=4 Hz), 7.31-7.33(2H, m), 7.47-7.47 (1H, d, J=1.5 Hz), 8.14 (1H, s)

Example 784-Amino-1-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-piperidine-4-carboxylic acid3,4-dichloro-benzylamide

The title compound was prepared as described for Example 69. LC-MS(LCT2) m/z 419 [M+H⁺], R_(t) 3.65 min.

¹H NMR (MeOD) δ 1.60-1.62 (2H, m), 2.18-2.24 (2H, m), 3.65-3.70 (2H, m),4.37 (2H, s), 4.48-4.50 (2H, m), 6.64 (1H, d, J=4 Hz), 7.13 (1H, d, J=4Hz), 7.22-7.24 (1H, m), 7.46-7.48 (2H, m), 8.14 (1H, s)

Example 794-(4-Chloro-benzyloxymethyl)-1-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-piperidin-4-ylamine

79A. 4-tert-Butoxycarbonylamino-4-hydroxymethyl-piperidine-1-carboxylicacid tert-butyl ester

A 1M solution of lithium aluminium hydride in tetrahydrofuran (1.66 mL,1.66 mmol) was added dropwise to a cooled (0° C.) solution of4-tert-butoxycarbonylamino-piperidine-1,4-dicarboxylic acidmono-tert-butyl ester (400 mg, 1.1 mmol) in dry tetrahydrofuran (5 mL).The solution was stirred for 3 h at rt under nitrogen. Water (172 μL)and 10% sodium hydroxide aq (232 μL) were added and the mixture wasstirred for 2 h. Further water (172 □L) was added and the mixture wasfiltered through a pad of celite and washed with diethyl ether. Thecrude product was purified by flash column chromatography on silica,eluting with 10% methanol in dichloromethane, to give4-tert-butoxycarbonylamino-4-hydroxymethyl-piperidine-1-carboxylic acidtert-butyl ester (178 mg, 0.54 mmol, 49%). LC-MS (LCT2) m/z 353 [M+Na⁺],R_(t) 6.67 min.

79B.4-tert-Butoxycarbonylamino-4-(4-chloro-benzyloxymethyl)-piperidine-1-carboxylicacid tert-butyl ester

Sodium hydride (60% suspension in oil, 4.9 mg, 0.11 mmol) was added insmall portions to a cooled (0° C.) solution of4-tert-butoxycarbonylamino-4-hydroxymethyl-piperidine-1-carboxylic acidtert-butyl ester (19 mg, 0.057 mmol) in dry DMF (0.2 mL). The suspensionwas stirred vigorously at 0° C. for 15 min followed by addition of4-chlorobenzyl bromide (14 mg, 0.066 mmol). After stirring for 45 min at0° C., the reaction mixture was warmed to rt. When TLC showed completeconsumption of the starting material, the reaction mixture was partionedbetween ethyl acetate (5 mL) and water (2 mL). The aqueous phase wasfurther extracted with ethyl acetate (5 mL). The combined organic layerswere dried (Mg₂SO₄), filtered and concentrated. Flash columnchromatography on silica, eluting with 1% methanol in dichloromethane,gave4-tert-butoxycarbonylamino-4-(4-chloro-benzyloxymethyl)-piperidine-1-carboxylicacid tert-butyl ester (6 mg, 0.013 mmol, 22%). LC-MS (LCT2) m/z 477[M+Na⁺], R_(t) 8.74 min.

79C. 4-(4-Chloro-benzyloxymethyl)-piperidin-4-ylamine dihydrochloride

A 4M solution of HCl in dioxane (0.68 ml, 2.7 mmol) was added dropwiseto a solution of4-tert-butoxycarbonylamino-4-(4-chloro-benzyloxymethyl)-piperidine-1-carboxylicacid tert-butyl ester (12 mg, 0.028 mmol) in methanol (1 mL). Thesolution was stirred at rt for 17 h. The solvents were removed byevaporation to give 4-(4-chloro-benzyloxymethyl)-piperidin-4-ylaminedihydrochloride (9.2 mg, 0.028 mmol, 100%) that was used in the nextstep without further purification.

¹H NMR (500 MHz, CD₃OD): 2.12-2.24 (4H, m), 3.22-3.32 (2H, m), 3.42-3.45(2H, m), 3.75 (2H, s), 4.66 (2H, s), 7.38-7.43 (4H, m).

79D.4-(4-Chloro-benzyloxymethyl)-1-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-piperidin-4-ylamine

A degassed mixture of 4-(4-chloro-benzyloxymethyl)-piperidin-4-ylaminedihydrochloride (9.2 mg, 0.028 mmol),4-chloro-7H-pyrrolo[2,3-d]pyrimidine (5.9 mg, 0.035 mmol), triethylamine(36 uL, 0.2 mmol) and n-butanol (0.35 mL) was stirred at 100° C. for 17h. The solvents were removed by evaporation. The crude mixture waspurified on an SCX-II acid resin, eluting with methanol then 2Mammonia/methanol, and then by preparative TLC eluting with 10% methanolin dichloromethane, to give4-(4-chloro-benzyloxymethyl)-1-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-piperidin-4-ylamine(8.2 mg, 0.022 mmol, 78%). LC-MS (LCT2) m/z 372 [M+H⁺], R_(t) 3.19 min.

¹H NMR (MeOD) δ 1.66-1.70 (2H, m), 1.86-1.88 (2H, m), 3.47 (2H, s),3.95-3.98 (2H, m), 4.03-4.06 (2H, m), 4.57 (2H, s), 6.62 (1H, d, J=4Hz), 7.13 (1H, d, J=4 Hz), 7.34-7.37 (4H, m), 8.14 (1H, s)

Example 804-Amino-1-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-piperidine-4-carboxylic acid2,4-difluoro-benzylamide

The title compound was prepared as described for Example 69. LC-MS(LCT2) m/z 387 [M+H⁺], R_(t) 2.46 min.

¹H NMR (MeOD) δ 1.59-1.61 (2H, m), 2.18-2.24 (2H, m), 3.66-3.71 (2H, m),4.43 (2H, s), 4.46-4.49 (2H, m), 6.63 (1H, d, J=4 Hz), 6.92-6.96 (2H,m), 7.13 (1H, d, J=4 Hz), 7.84-7.87 (1H, m), 8.14 (1H, s)

Example 81 [4-Amino-1-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-piperidin-4-yl]-(3,4-dihydro-1H-isoquinolin-2-yl)-methanone

The title compound was prepared according to the method described inExample 69. LC-MS (LCT2) m/z 377 [M+H⁺], R_(t) 2.73 min.

¹H NMR (CD₃OD) δ 1.70-1.80 (2H, m), 2.25-2.35 (2H, m), 2.80-2.95 (2H,m), 4.04-4.08 (6H, m), 4.90-5.00 (2H, m), 6.63 (1H, s), 7.05-7.16 (5H,m), 8.14 (1H, s).

Example 82[4-Amino-1-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-piperidin-4-yl]-(2-phenyl-pyrrolidin-1-yl)-methanone

The title compound was prepared according to the method described inExample 69. LC-MS (LCT2) m/z 391 [M+H⁺], R_(t) 2.68 min.

¹H NMR (CD₃OD) δ 1.50-2.31 (8H, m), 3.65-4.04 (5H, m), 4.20-4.40 (1H,m), 5.10-5.20 (1H, m), 6.63 (1H, s), 7.12-7.29 (6H, m), 8.11 (1H, s).

Example 83 4-(4-Chlorobenzyl)-1-(1H-pyrazolo[3,4-b]pyridin-4-yl)-piperidin-4-ylamine

83A.4-[4-Amino-4-(4-chlorobenzyl)-piperidin-1-yl]-1H-pyrazolo[3,4-b]pyridine-5-carboxylicacid ethyl ester

A mixture of 4-chloro-1H-pyrrolo[2,3-b]pyridine-5-carboxylic acid ethylester (Example 68A) (50 mg, 0.22 mmol),4-(4-chlorobenzyl)-piperidin-4-ylamine hydrochloride (65 mg, 0.22 mmol)and triethylamine (150μ) in n-butanol (1.5 mL) was irradiated in amicrowave reactor (200 W) for 1 hr at 100° C. After cooling, the solventwas evaporated. The solids obtained were dissolved in ethyl acetate, theorganic layer was washed with aqueous sodium hydrogen carbonate, brineand then dried (Na₂SO₄). Evaporation of the organic solution gave4-[4-amino-4-(4-chlorobenzyl)-piperidin-1-yl]-1H-pyrazolo[3,4-b]pyridine-5-carboxylicacid ethyl ester as an off-white solid (80 mg, 87%). LC-MS (LCT2) m/z415 [M+H⁺], R_(t) 3.99 mm.

¹H NMR (d₆-DMSO) δ 1.30 (3H, t, J=7 Hz), 1.36 (2H, m), 1.68 (2H, m),2.68 (2H, s), 3.50 (2H, m), 3.60 (2H, m), 4.25 (2H, q, J=7 Hz), 7.25(2H, d, J=8.3 Hz), 7.35 (2H, d, J=8.3 Hz), 8.20 (1H, s), 8.40 (1H, s),13.50 (1H, s)

83B.4-(4-Chlorobenzyl)-1-(1H-pyrazolo[3,4-b]pyridin-4-yl)-piperidin-4-ylamine

4-[4-Amino-4-(4-chlorobenzyl)-piperidin-1-yl]-1H-pyrazolo[3,4-b]pyridine-5-carboxylicacid ethyl ester (55 mg, 0.13 mmol) was suspended in 2M potassiumhydroxide (1.5 mL) and irradiated in a microwave reactor (250 W) for 2hours at 120° C. After cooling, water (2 mL) was added and the solidsformed were collected by filtration. The filtrate was extracted withethyl acetate (2×4 mL) and dried (Na₂SO₄). The extracts were evaporatedand the resulting yellow solids were combined with the previous materialand dissolved in acetone (10 mL) and n-hexanes (2 mL). The solvents wereconcentrated until precipitation occurred. The solids were collected byfiltration and washed with n-hexanes to give4-(4-chlorobenzyl)-1-(1H-pyrazolo[3,4-b]pyridin-4-yl)-piperidin-4-ylamineas a light yellow powder (26 mg, 57%). LC-MS (LCT2) m/z 342 [M+H⁺],R_(t) 2.07 min.

¹H NMR (d₆-DMSO) δ 1.38 (2H, m), 1.62 (2H, m), 2.65 (2H, s), 3.50 (2H,m), 3.85 (2H, m), 6.35 (1H, d, J=5 Hz), 7.27 (2H, d, J=8 Hz), 7.34 (2H,d, J=8 Hz), 8.02 (1H, d, J=5 Hz), 8.15 (1H, s), 13.13 (1H, s)

Example 844-(4-tert-Butyl-benzyl)-1-(1H-pyrazolo[3,4-b]pyridine-4-yl)-piperidin-4-ylamine

84A.4-[4-Amino-4-(4-tert-butyl-benzyl)-piperidin-1-yl]-1H-pyrazolo[3,4-b]pyridine-5-carboxylicacid ethyl ester

A mixture of 4-chloro-1H-pyrrolo[2,3-b]pyridine-5-carboxylic acid ethylester (Example 68A) (50 mg, 0.22 mmol),4-(4-tert-butyl-benzyl)-piperidin-4-ylamine hydrochloride (70.8 mg, 0.22mmol) and triethylamine (150 μL) in n-butanol (1.5 mL) was irradiated ina microwave reactor (200 W) for 1 hour at 100° C. After cooling, thesolvent was evaporated and the residue was purified by columnchromatography (EtOAc-MeOH 4:1) to give an off-white solid (63 mg, 65%).LC-MS (LCT2) m/z 436 [M+H⁺], R_(t) 5.01 min.

¹H NMR (d₆-DMSO) δ 1.38 (9H, s), 1.38 (3H, t, J=7 Hz), 1.85 (4H, m), 3.0(2H, s), 3.62 (2H, m), 3.70 (2H, m), 4.25 (2H, q, J=7 Hz), 7.15 (2H, d,J=8.2 Hz), 7.30 (2H, d, J=8.2 Hz), 8.20 (1H, s), 8.40 (1H, s), 13.45(1H, s)

84B.4-(4-tert-Butyl-benzyl)-1-(1H-pyrazolo[3,4-b]pyridin-4-yl)-piperidin-4-ylamine

4-[4-Amino-4-(4-tert-butyl-benzyl)-piperidin-1-yl]-1H-pyrazolo[3,4-b]pyridine-5-carboxylicacid ethyl ester (23 mg, 0.053 mmol) was suspended in 2M potassiumhydroxide (1 mL) and irradiated in a microwave reactor (250 W) for 2hours at 120° C. After cooling, water (2 mL) was added and the aqueouslayer was extracted with ethyl acetate (2×4 mL). The organic layers weredried (Na₂SO₄) and concentrated to give a yellow solid (9 mg, 47%).LC-MS (LCT2) m/z 364 [M+H⁺], R_(t) 2.80 min.

¹H NMR (CD₃OD) δ 1.32 (9H, s), 1.63 (2H, m), 1.86 (2H, m), 2.80 (2H, s),3.70 (2H, m), 3.95 (2H, m), 6.46 (1H, d, J=5.8 Hz), 7.20 (2H, J=8 Hz),7.40 (2H, J=8 Hz), 8.08 (1H, d, J=5.8 Hz), 8.20 (1H, s)

Example 854-(4-tert-Butyl-benzyl)-1-(1H-pyrrolo[2,3-b]pyridin-4-yl)-piperidin-4-ylamine

The title compound was prepared as described for Example 54. LC-MS(LCT2) m/z 363 [M+H⁺], R_(t) 3.19 min.

¹H NMR (CD₃OD) δ 1.33 (9H, s), 1.60-1.65 (2H, m), 1.85-1.90 (2H, m),2.81 (2H, s), 3.48-3.52 (2H, m), 3.72-3.78 (2H, m), 6.50-6.52 (2H, m),7.17-7.21 (3H, m), 7.39 (2H, d, J=8 Hz), 7.92 (1H, d, J=5 Hz)

Example 86N-[4-Amino-1-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-piperidin-4-ylmethyl]-4-chloro-benzamide

86A. 4-tert-Butoxycarbonylamino-4-carbamoyl-piperidine-1-carboxylic acidtert-butyl ester

1-Hydroxybenzotriazole hydrate (150 mg, 1.1 mmol) and1-(3-dimethylaminopropyl)-3-ethyl-carbodiimide hydrochloride (214 mg,1.1 mmol) were added to a stirred solution of4-tert-butoxycarbonylamino-piperidine-1,4-dicarboxylic acidmono-tert-butyl ester (149 mg, 0.44 mmol) in DMF (9 mL). The reactionmixture was stirred for 80 minutes, and ammonium hydroxide (1.2 mL,ammonia sol. aq.) was added. After stirring for a further 20 hours atroom temperature, brine (18 mL) and water (3 mL) were added to thereaction mixture. The aqueous phase was extracted with ethyl acetate(2×12 mL) and the combined organic phases were dried (Mg₂SO₄), filteredand concentrated to give4-tert-butoxycarbonylamino-4-carbamoyl-piperidine-1-carboxylic acidtert-butyl ester (147 mg, 0.43 mmol, 97%). LC-MS (LCT2) m/z 366 [M+Na⁺],R_(t) 16.63 min.

86B. 4-Aminomethyl-4-tert-butoxycarbonylamino-piperidine-1-carboxylicacid tert-butyl ester

A 1M solution of borane complex in THF (2.25 mL, 2.25 mmol) was added toa cooled solution (0° C.) of4-tert-butoxycarbonylamino-4-carbamoyl-piperidine-1-carboxylic acidtert-butyl ester (107 mg, 0.3 mmol) in THF (4.3 mL). After stirring for5 minutes at 0° C. the reaction mixture was allowed to warm to roomtemperature. The reaction mixture was further warmed to 60° C. andstirred overnight. The reaction mixture was cooled to room temperatureand methanol (5.1 mL) was added. After stirring for 30 minutes, thesolvents were removed by evaporation. The reaction mixture waspartitioned between an aqueous saturated solution of ammonium chloride(10 mL) and dichloromethane (10 mL). After further extraction of theaqueous phase with dichloromethane (20 mL), the combined organic phaseswere dried (Mg₂SO₄), filtered and concentrated. Flash columnchromatography on silica, eluting with 5% methanol in dichloromethane,gave 4-aminomethyl-4-tert-butoxycarbonylamino-piperidine-1-carboxylicacid tert-butyl ester (5.5 mg, 0.017 mmol, 6%). LC-MS (LCT2) m/z 352[M+Na⁺], R_(t) 7.16 min.

86C.4-tert-Butoxycarbonylamino-4-[(4-chloro-benzoylamino)-methyl]-piperidine-1-carboxylicacid tert-butyl ester

To a solution of4-aminomethyl-4-tert-butoxycarbonylamino-piperidine-1-carboxylic acidtert-butyl ester (12.2 mg, 0.037 mmol) and triethylamine (16 μL, 0.12mmol) in dry dichloromethane (4 mL) was added 4-chlorobenzoyl chloride(5 μL, 0.037 mmol). After stirring for 18 hours at room temperature, thereaction mixture was partionated between dichloromethane (2 mL) andwater (1 mL) with 10% aqueous sodium hydroxide (0.1 mL). The two layerswere separated and the aqueous phase was further extracted withdichloromethane (2 mL). The combined organic layers were dried (Mg₂SO₄),filtered and concentrated. Preparative TLC, eluting with 10%methanol-dichloromethane, gave4-tert-butoxycarbonylamino-4-[(4-chloro-benzoylamino)-methyl]-piperidine-1-carboxylicacid tert-butyl ester (6 mg, 0.013 mmol, 35%). LC-MS (LCT2) m/z 490[M+Na⁺], R_(t) 8.20 min.

86D. N-(4-Amino-piperidin-4-ylmethyl)-4-chloro-benzamide dihydrochloride

A 4M solution of HCl in dioxane (0.3 ml, 1.2 mmol) was added dropwise toa solution of4-tert-butoxycarbonylamino-4-[(4-chloro-benzoylamino)-methyl]-piperidine-1-carboxylicacid tert-butyl ester (5.8 mg, 0.012 mmol) in methanol (0.5 mL). Thesolution was stirred at room temperature for 17 hours. The solvents wereconcentrated to give N-(4-amino-piperidin-4-ylmethyl)-4-chloro-benzamidedihydrochloride (6.1 mg, quantitative) that was used in the next stepwithout further purification. ¹H NMR (CD₃OD) δ 2.23-2.30 (4H, m),3.46-3.61 (4H, m), 3.89 (2H, s), 7.58 (2H, d, J=7 Hz), 8.03 (2H, d, J=7Hz).

86E.N-[4-Amino-1-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-piperidin-4-ylmethyl]-4-chloro-benzamide

A degassed mixture of crudeN-(4-amino-piperidin-4-ylmethyl)-4-chloro-benzamide dihydrochloride (6.1mg), 4-chloro-7H-pyrrolo[2,3-d]pyrimidine (2.6 mg, 0.016 mmol),triethylamine (16 μL, 0.09 mmol) and n-butanol (0.3 mL) was stirred at100° C. for 17 hours. The solvents were concentrated. The crude mixturewas first purified on an SCX-II acidic resin, eluting with methanol then2M ammonia-methanol, and then by preparative TLC, eluting with 15%methanol-dichloromethane, to giveN-[4-amino-1-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-piperidin-4-ylmethyl]-4-chloro-benzamide(3.3 mg, 0.009 mmol, 69% over 2 steps). LC-MS (LCT2) m/z 385 [M+H⁺],R_(t) 2.58 min.

¹H NMR (CD₃OD) δ 1.79-1.81 (2H, m), 1.95-1.97 (2H, m), 3.67 (2H, s),4.20-4.17 (4H, m), 6.72 (1H, d, J=5 Hz), 7.23 (1H, d, J=5 Hz), 7.58 (2H,d, J=7 Hz), 7.96 (2H, d, J=7 Hz), 8.24 (1H, s).

ExampleS 87 TO 90

By following the methods described above, or methods analogous thereto,the compounds of Examples 87 to 90 were prepared.

Example 874-Biphenyl-4-ylmethyl-1-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-piperidin-4-ylamine

Example 884-Biphenyl-2-ylmethyl-1-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-piperidin-4-ylamine

Example 894-(2-Methoxy-benzyl)-1-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-piperidin-4-ylamine

Example 904-Naphthalen-1-ylmethyl-1-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-piperidin-4-ylamine

ExampleS 91 TO 94

By following the methods described above, or methods analogous thereto,the compounds of Examples 91 to 94 are prepared.

Example 914-Amino-1-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-piperidine-4-carboxylic acid4-chloro-2-fluoro-benzylamide

Example 924-Amino-1-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-piperidine-4-carboxylic acid(biphenyl-3-ylmethyl)-amide

Example 934-Biphenyl-3-ylmethyl-1-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-piperidin-4-ylamine

Example 944-(6-Chloro-biphenyl-3-ylmethyl)-1-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-piperidin-4-ylamine

Biological Activity Example 95 Measurement of PKA Kinase InhibitoryActivity (IC₅₀)

Compounds of the invention can be tested for PK inhibitory activityusing the PKA catalytic domain from Upstate Biotechnology (#14-440) andthe 9 residue PKA specific peptide (GRTGRRNSI), also from UpstateBiotechnology (#12-257), as the substrate. A final concentration of 1 nMenzyme is used in a buffer that includes 20 mM MOPS pH 7.2, 40 μMATP/γ³³P-ATP and 50 mM substrate. Compounds are added indimethylsulphoxide (DMSO) solution to a final DMSO concentration of2.5%. The reaction is allowed to proceed for 20 minutes before additionof excess orthophosphoric acid to quench activity. Unincorporatedγ³³P-ATP is then separated from phosphorylated proteins on a MilliporeMAPH filter plate. The plates are washed, scintillant is added and theplates are then subjected to counting on a Packard Topcount.

The % inhibition of the PKA activity is calculated and plotted in orderto determine the concentration of test compound required to inhibit 50%of the PKA activity (IC₅₀).

Following the protocol described above, the IC₅₀ values of the compoundsof Examples 1, 3, 6, 8, 10, 11, 12, 13, 14, 17-20, 25, 26, 28, 31-32,38, 40, 42 and 44 have been found to be less than 10 μM whilst thecompounds of Examples 4, 5, 7 and 9 each have IC₅₀ values of less than50 μM.

Example 96 Measurement of PKB Kinase Inhibitory Activity (IC₅₀)

The inhibition of protein kinase B (PKB) activity by compounds can bedetermined essentially as described by Andjelkovic et al. (Mol. Cell.Biol. 19, 5061-5072 (1999)) but using a fusion protein described asPKB-PIF and described in full by Yang et al (Nature Structural Biology9, 940-944 (2002)). The protein is purified and activated with PDK1 asdescribed by Yang et al. The peptide AKTide-2T(H-A-R-K-R-E-R-T-Y-S-F-G-H-H-A-OH) obtained from Calbiochem (#123900) isused as a substrate. A final concentration of 0.6 nM enzyme is used in abuffer that includes 20 mM MOPS pH 7.2, 30 μM ATP/γ³³P-ATP and 25 μMsubstrate.

Compounds are added in DMSO solution to a final DMSO concentration of2.5%. The reaction is allowed to proceed for 20 minutes before additionof excess orthophosphoric acid to quench activity. The reaction mixtureis transferred to a phosphocellulose filter plate where the peptidebinds and the unused ATP is washed away. After washing, scintillant isadded and the incorporated activity measured by scintillation counting.

The % inhibition of the PKB activity is calculated and plotted in orderto determine the concentration of test compound required to inhibit 50%of the PKB activity (IC₅₀).

Following the protocol described above, the IC₅₀ values of the compoundsof Examples 1 to 4, 6, 8 and 10 to 52 have been found to be less than 10μM whilst the compounds of Examples 5, 7 and 9 each have IC₅₀ values ofless than 50 μM.

Example 97 Anti-Proliferative Activity

The anti-proliferative activities of compounds of the invention aredetermined by measuring the ability of the compounds to inhibition ofcell growth in a number of cell lines. Inhibition of cell growth ismeasured using the Alamar Blue assay (Nociari, M. M, Shalev, A., Benias,P., Russo, C. Journal of Immunological Methods 1998, 213, 157-167). Themethod is based on the ability of viable cells to reduce resazurin toits fluorescent product resorufin. For each proliferation assay cellsare plated onto 96 well plates and allowed to recover for 16 hours priorto the addition of inhibitor compounds for a further 72 hours. At theend of the incubation period 10% (v/v) Alamar Blue is added andincubated for a further 6 hours prior to determination of fluorescentproduct at 535 nM ex/590 nM em. In the case of the non-proliferatingcell assay cells are maintained at confluence for 96 hour prior to theaddition of inhibitor compounds for a further 72 hours. The number ofviable cells is determined by Alamar Blue assay as before. All celllines are obtained from ECACC (European Collection of cell Cultures) orATCC.

In particular, compounds of the invention were tested against the PC3cell line (ATCC Reference: CRL-1435) derived from human prostateadenocarcinoma. Many compounds of the invention were found to have IC₅₀values of less than 25 μM in this assay and preferred compounds haveIC₅₀ values of less than 15 μM.

Pharmaceutical Formulations Example 98 (i) Tablet Formulation

A tablet composition containing a compound of the formula (I) isprepared by mixing 50 mg of the compound with 197 mg of lactose (BP) asdiluent, and 3 mg magnesium stearate as a lubricant and compressing toform a tablet in known manner.

(ii) Capsule Formulation

A capsule formulation is prepared by mixing 100 mg of a compound of theformula (I) with 100 mg lactose and filling the resulting mixture intostandard opaque hard gelatin capsules.

(iii) Injectable Formulation I

A parenteral composition for administration by injection can be preparedby dissolving a compound of the formula (I) (e.g. in a salt form) inwater containing 10% propylene glycol to give a concentration of activecompound of 1.5% by weight. The solution is then sterilised byfiltration, filled into an ampoule and sealed.

(iv) Injectable Formulation II

A parenteral composition for injection is prepared by dissolving inwater a compound of the formula (I) (e.g. in salt form) (2 mg/ml) andmannitol (50 mg/ml), sterile filtering the solution and filling intosealable 1 ml vials or ampoules.

(iv) Subcutaneous Injection Formulation

A composition for sub-cutaneous administration is prepared by mixing acompound of the formula (I) with pharmaceutical grade corn oil to give aconcentration of 5 mg/ml. The composition is sterilised and filled intoa suitable container.

EQUIVALENTS

The foregoing examples are presented for the purpose of illustrating theinvention and should not be construed as imposing any limitation on thescope of the invention. It will readily be apparent that numerousmodifications and alterations may be made to the specific embodiments ofthe invention described above and illustrated in the examples withoutdeparting from the principles underlying the invention. All suchmodifications and alterations are intended to be embraced by thisapplication.

1-105. (canceled)
 106. A method for treating a disease or condition comprising or arising from abnormal cell growth or abnormally arrested cell death in a mammal, which method comprises administering to the mammal a therapeutically effective amount of a compound of the formula (I):

or a salt, solvate, tautomer or N-oxide thereof, wherein T is N or a group CR⁵; J¹-J² represents a group selected from N═C(R⁶), (R⁷)C═N, (R⁸)N—C(O), (R⁸)₂C—C(O), N═N and (R⁷)C═C(R⁶); E is a monocyclic carbocyclic or heterocyclic group of 5 or 6 ring members wherein the heterocyclic group contains up to 3 heteroatoms selected from O, N and S; Q¹ is a bond or a saturated hydrocarbon linker group containing from 1 to 3 carbon atoms, wherein one of the carbon atoms in the linker group may optionally be replaced by an oxygen or nitrogen atom, or an adjacent pair of carbon atoms may be replaced by CONR^(q) or NR^(q)CO where R^(q) is hydrogen, C₁₋₄ alkyl or cyclopropyl, or R^(q) is a C₁₋₄ alkylene chain that links to R¹ or to another carbon atom of Q¹ to form a cyclic moiety; and wherein the carbon atoms of the linker group Q¹ may optionally bear one or more substituents selected from fluorine and hydroxy; Q² is a bond or a saturated hydrocarbon linker group containing from 1 to 3 carbon atoms, wherein one of the carbon atoms in the linker group may optionally be replaced by an oxygen or nitrogen atom; and wherein the carbon atoms of the linker group may optionally bear one or more substituents selected from fluorine and hydroxy, provided that the hydroxy group when present is not located at a carbon atom α with respect to the G group; G is selected from hydrogen, NR²R³, OH and SH with the proviso that when E is aryl or heteroaryl and Q² is a bond, then G is hydrogen; R¹ is hydrogen or an aryl or heteroaryl group, with the proviso that when R¹ is hydrogen and G is NR²R³, then Q² is a bond; R² and R³ are independently selected from hydrogen; C₁₋₄ hydrocarbyl and C₁₋₄ acyl wherein the hydrocarbyl and acyl groups are optionally substituted by one or more substituents selected from fluorine, hydroxy, cyano, amino, methylamino, dimethylamino, methoxy and a monocyclic or bicyclic aryl or heteroaryl group; or R² and R³ together with the nitrogen atom to which they are attached form a cyclic group selected from an imidazole group and a saturated monocyclic heterocyclic group having 4-7 ring members and optionally containing a second heteroatom ring member selected from O and N; or one of R² and R³ together with the nitrogen atom to which they are attached and one or more atoms from the group Q² form a saturated monocyclic heterocyclic group having 4-7 ring members and optionally containing a second heteroatom ring member selected from O and N; or NR²R³ when present and a carbon atom of linker group Q² to which it is attached together form a cyano group; and R⁴, R⁶ and R⁸ are each independently selected from hydrogen, halogen, C₁₋₅ saturated hydrocarbyl, cyano, CONH₂, CONHR⁹, CF₃, NH₂, NHCOR⁹ and NHCONHR⁹; R⁵ and R⁷ are each independently selected from hydrogen, halogen, C₁₋₅ saturated hydrocarbyl, cyano and CF₃; R⁹ is phenyl or benzyl each optionally substituted by one or substituents selected from halogen, hydroxy, trifluoromethyl, cyano, nitro, carboxy, amino, mono- or di-C₁₋₄ hydrocarbylamino; a group R^(a)-R^(b) wherein R^(a) is a bond, O, CO, X¹C(X²), C(X²)X¹, X¹C(X²)X¹, S, SO, SO₂, NR^(c), SO₂NR^(c) or NR^(c)SO₂; and R^(b) is selected from hydrogen, heterocyclic groups having from 3 to 12 ring members, and a C₁₋₈ hydrocarbyl group optionally substituted by one or more substituents selected from hydroxy, oxo, halogen, cyano, nitro, carboxy, amino, mono- or di-C₁₋₄ hydrocarbylamino, carbocyclic and heterocyclic groups having from 3 to 12 ring members and wherein one or more carbon atoms of the C₁₋₈ hydrocarbyl group may optionally be replaced by O, S, SO, SO₂, NR^(c), X¹C(X²), C(X²)X¹ or X¹C(X²)X¹; R^(c) is selected from hydrogen and C₁₋₄ hydrocarbyl; and X¹ is O, S or NR^(c) and X² is ═O, ═S or ═NR^(c).
 107. A method according to claim 106 wherein the compound is a compound of the formula (Ia):

or a salt, solvate, tautomer or N-oxide thereof, wherein T is N or a group CR⁵; J¹-J² represents a group selected from N═C(R⁶), (R⁷)C═N, (R⁸)N—C(O), (R⁸)₂C—C(O), N═N and (R⁷)C═C(R⁶); E is a monocyclic carbocyclic or heterocyclic group of 5 or 6 ring members wherein the heterocyclic group contains up to 3 heteroatoms selected from O, N and S; Q¹ and Q² are the same or different and are each a bond or a saturated hydrocarbon linker group containing from 1 to 3 carbon atoms, wherein one of the carbon atoms in the linker group may optionally be replaced by an oxygen or nitrogen atom; and wherein the carbon atoms of the or each linker group Q¹ and Q² may optionally bear one or more substituents selected from fluorine and hydroxy, provided that the hydroxy group when present is not located at a carbon atom a with respect to the G group; G is selected from hydrogen, NR²R³, OH and SH with the proviso that when E is aryl or heteroaryl and Q² is a bond, then G is hydrogen; R¹ is hydrogen or an aryl or heteroaryl group, with the proviso that when R¹ is hydrogen and G is NR²R³, then Q² is a bond; R² and R³ are independently selected from hydrogen; C₁₋₄ hydrocarbyl and C₁₋₄ acyl wherein the hydrocarbyl and acyl groups are optionally substituted by one or more substituents selected from fluorine, hydroxy, amino, methylamino, dimethylamino, methoxy and a monocyclic or bicyclic aryl or heteroaryl group; or R² and R³ together with the nitrogen atom to which they are attached form a cyclic group selected from an imidazole group and a saturated monocyclic heterocyclic group having 4-7 ring members and optionally containing a second heteroatom ring member selected from O and N; or one of R² and R³ together with the nitrogen atom to which they are attached and one or more atoms from the group Q² form a saturated monocyclic heterocyclic group having 4-7 ring members and optionally containing a second heteroatom ring member selected from O and N; or NR²R³ when present and a carbon atom of linker group Q² to which it is attached together form a cyano group; and R⁴, R⁶ and R⁸ are each independently selected from hydrogen, halogen, C₁₋₅ saturated hydrocarbyl, cyano, CONH₂, CONHR⁹, CF₃, NH₂, NHCOR⁹ and NHCONHR⁹; R⁵ and R⁷ are each independently selected from hydrogen, halogen, C₁₋₅ saturated hydrocarbyl, cyano and CF₃; R⁹ is phenyl or benzyl each optionally substituted by one or substituents selected from halogen, hydroxy, trifluoromethyl, cyano, nitro, carboxy, amino, mono- or di-C₁₋₄ hydrocarbylamino; a group R^(a)-R^(b) wherein R^(a) is a bond, O, CO, X¹C(X²), C(X²)X¹, X¹C(X²)X¹, S, SO, SO₂, NR^(c), SO₂NR^(c) or NR^(c)SO₂; and R^(b) is selected from hydrogen, heterocyclic groups having from 3 to 12 ring members, and a C₁₋₈ hydrocarbyl group optionally substituted by one or more substituents selected from hydroxy, oxo, halogen, cyano, nitro, carboxy, amino, mono- or di-C₁₋₄ hydrocarbylamino, carbocyclic and heterocyclic groups having from 3 to 12 ring members and wherein one or more carbon atoms of the C₁₋₈ hydrocarbyl group may optionally be replaced by O, S, SO, SO₂, NR^(c), X¹C(X²), C(X²)X¹ or X¹C(X²)X¹; R^(c) is selected from hydrogen and C₁₋₄ hydrocarbyl; and X¹ is O, S or NR^(c) and X² is ═O, ═S or ═NR^(c).
 108. A method according to claim 106 wherein the compound is a compound of the formula (Ib):

or a salt, solvate, tautomer or N-oxide thereof, wherein T is N or a group CR⁵; J¹-J² represents a group selected from N═C(R⁶), (R⁷)C═N, (R⁸)N—C(O), (R⁸)₂C—C(O), N═N and (R⁷)C═C(R⁶); E is a monocyclic carbocyclic or heterocyclic group of 5 or 6 ring members wherein the heterocyclic group contains up to 3 heteroatoms selected from O, N and S; Q¹ and Q² are the same or different and are each a bond or a saturated hydrocarbon linker group containing from 1 to 3 carbon atoms, wherein one of the carbon atoms in the linker group may optionally be replaced by an oxygen or nitrogen atom; and wherein the carbon atoms of the or each linker group Q¹ and Q² may optionally bear one or more substituents selected from fluorine and hydroxy, provided that the hydroxy group when present is not located at a carbon atom a with respect to the G group; G is selected from hydrogen, NR²R³, OH and SH with the proviso that when E is aryl or heteroaryl and Q² is a bond, then G is hydrogen; R¹ is hydrogen or an aryl or heteroaryl group, with the proviso that when R¹ is hydrogen and G is NR²R³, then Q² is a bond; R² and R³ are independently selected from hydrogen; C₁₋₄ hydrocarbyl and C₁₋₄ acyl wherein the hydrocarbyl and acyl groups are optionally substituted by a monocyclic or bicyclic aryl or heteroaryl group; or R² and R³ together with the nitrogen atom to which they are attached form a saturated monocyclic heterocyclic group having 4-7 ring members and optionally containing a second heteroatom ring member selected from O and N; or one of R² and R³ together with the nitrogen atom to which they are attached and one or more atoms from the group Q² form a saturated monocyclic heterocyclic group having 4-7 ring members and optionally containing a second heteroatom ring member selected from O and N; or NR²R³ when present and a carbon atom of linker group Q² to which it is attached together form a cyano group; and R⁴, R⁶ and R⁸ are each independently selected from hydrogen, halogen, C₁₋₅ saturated hydrocarbyl, cyano, CONH₂, CONHR⁹, CF₃, NH₂, NHCOR⁹ or NHCONHR⁹; R⁵ and R⁷ are each independently selected from hydrogen, halogen, C₁₋₅ saturated hydrocarbyl, cyano and CF₃; R⁹ is phenyl or benzyl each optionally substituted by one or substituents selected from halogen, hydroxy, trifluoromethyl, cyano, nitro, carboxy, amino, mono- or di-C₁₋₄ hydrocarbylamino; a group R^(a)-R^(b) wherein R^(a) is a bond, O, CO, X¹C(X²), C(X²)X¹, X¹C(X²)X¹, S, SO, SO₂, NR^(c), SO₂NR^(c) or NR^(c)SO₂; and R^(b) is selected from hydrogen, heterocyclic groups having from 3 to 12 ring members, and a C₁₋₈ hydrocarbyl group optionally substituted by one or more substituents selected from hydroxy, oxo, halogen, cyano, nitro, carboxy, amino, mono- or di-C₁₋₄ hydrocarbylamino, carbocyclic and heterocyclic groups having from 3 to 12 ring members and wherein one or more carbon atoms of the C₁₋₈ hydrocarbyl group may optionally be replaced by O, S, SO, SO₂, NR^(c), X¹C(X²), C(X²)X¹ or X¹C(X²)X¹; R^(c) is selected from hydrogen and C₁₋₄ hydrocarbyl; and X¹ is O, S or NR^(c) and X² is ═O, ═S or ═NR^(c).
 109. A compound of the formula (Ic):

or salts, solvates, tautomers or N-oxides thereof, wherein T is N or a group CR⁵; J¹-J² represents a group selected from N═C(R⁶), (R⁷)C═N, (R⁸)N—C(O), (R⁸)₂C—C(O), N═N and (R⁷)C═C(R⁶); E is a monocyclic carbocyclic or heterocyclic group of 5 or 6 ring members wherein the heterocyclic group contains up to 3 heteroatoms selected from O, N and S; Q¹ is a bond or a saturated hydrocarbon linker group containing from 1 to 3 carbon atoms, wherein one of the carbon atoms in the linker group may optionally be replaced by an oxygen or nitrogen atom, or an adjacent pair of carbon atoms may be replaced by CONR^(q) or NR^(q)CO where R^(q) is hydrogen, C₁₋₄ alkyl or cyclopropyl, or R^(q) is a C₁₋₄ alkylene chain that links to R¹ or to another carbon atom of Q¹ to form a cyclic moiety; and wherein the carbon atoms of the linker group Q¹ may optionally bear one or more substituents selected from fluorine and hydroxy; Q² is a bond or a saturated hydrocarbon linker group containing from 1 to 3 carbon atoms, wherein one of the carbon atoms in the linker group may optionally be replaced by an oxygen or nitrogen atom; and wherein the carbon atoms of the linker group may optionally bear one or more substituents selected from fluorine and hydroxy, provided that the hydroxy group when present is not located at a carbon atom α with respect to the G group; and provided that when E is aryl or heteroaryl, then Q² is other than a bond; R¹ is an aryl or heteroaryl group; R² and R³ are independently selected from hydrogen; C₁₋₄ hydrocarbyl and C₁₋₄ acyl wherein the hydrocarbyl and acyl groups are optionally substituted by one or more substituents selected from fluorine, hydroxy, cyano, amino, methylamino, dimethylamino, methoxy and a monocyclic or bicyclic aryl or heteroaryl group; or R² and R³ together with the nitrogen atom to which they are attached form a saturated monocyclic heterocyclic group having 4-7 ring members and optionally containing a second heteroatom ring member selected from O and N; or one of R² and R³ together with the nitrogen atom to which they are attached and one or more atoms from the group Q² form a saturated monocyclic heterocyclic group having 4-7 ring members and optionally containing a second heteroatom ring member selected from O and N; or NR²R³ and a carbon atom of linker group Q² to which it is attached together form a cyano group; and R⁴, R⁶ and R⁸ are each independently selected from hydrogen, halogen, C₁₋₅ saturated hydrocarbyl, cyano, CONH₂, CONHR⁹, CF₃, NH₂, NHCOR⁹ or NHCONHR⁹; R⁵ and R⁷ are each independently selected from hydrogen, halogen, C₁₋₅ saturated hydrocarbyl, cyano and CF₃; R⁹ is phenyl or benzyl each optionally substituted by one or substituents selected from halogen, hydroxy, trifluoromethyl, cyano, nitro, carboxy, amino, mono- or di-C₁₋₄ hydrocarbylamino; a group R^(a)-R^(b) wherein R^(a) is a bond, O, CO, X¹C(X²), C(X²)X¹, X¹C(X²)X¹, S, SO, SO₂, NR^(c), SO₂NR^(c) or NR^(c)SO₂; and R^(b) is selected from hydrogen, heterocyclic groups having from 3 to 12 ring members, and a C₁₋₈ hydrocarbyl group optionally substituted by one or more substituents selected from hydroxy, oxo, halogen, cyano, nitro, carboxy, amino, mono- or di-C₁₋₄ hydrocarbylamino, carbocyclic and heterocyclic groups having from 3 to 12 ring members and wherein one or more carbon atoms of the C₁₋₈ hydrocarbyl group may optionally be replaced by O, S, SO, SO₂, NR^(c), X¹C(X²), C(X²)X¹ or X¹C(X²)X¹; R^(c) is selected from hydrogen and C₁₋₄ hydrocarbyl; and X¹ is O, S or NR^(c) and X² is ═O, ═S or ═NR^(c).
 110. A compound according to claim 109, of the formula (Id):

or salts, solvates, tautomers or N-oxides thereof, wherein T is N or a group CR⁵; J¹-J² represents a group selected from N═C(R⁶), (R⁷)C═N, (R⁸)N—C(O), (R⁸)₂C—C(O), N═N and (R⁷)C═C(R⁶); E is a monocyclic carbocyclic or heterocyclic group of 5 or 6 ring members wherein the heterocyclic group contains up to 3 heteroatoms selected from O, N and S; Q¹ and Q² are the same or different and are each a bond or a saturated hydrocarbon linker group containing from 1 to 3 carbon atoms, wherein one of the carbon atoms in the linker group may optionally be replaced by an oxygen or nitrogen atom; and wherein the carbon atoms of the or each linker group Q¹ and Q² may optionally bear one or more substituents selected from fluorine and hydroxy, provided that the hydroxy group when present is not located at a carbon atom a with respect to the G group; and provided that when E is aryl or heteroaryl, then Q² is other than a bond; R¹ is an aryl or heteroaryl group; R² and R³ are independently selected from hydrogen; C₁₋₄ hydrocarbyl and C₁₋₄ acyl wherein the hydrocarbyl and acyl groups are optionally substituted by one or more substituents selected from fluorine, hydroxy, amino, methylamino, dimethylamino, methoxy and a monocyclic or bicyclic aryl or heteroaryl group; or R² and R³ together with the nitrogen atom to which they are attached form a saturated monocyclic heterocyclic group having 4-7 ring members and optionally containing a second heteroatom ring member selected from O and N; or one of R² and R³ together with the nitrogen atom to which they are attached and one or more atoms from the group Q² form a saturated monocyclic heterocyclic group having 4-7 ring members and optionally containing a second heteroatom ring member selected from O and N; or NR²R³ and a carbon atom of linker group Q² to which it is attached together form a cyano group; and R⁴, R⁶ and R⁸ are each independently selected from hydrogen, halogen, C₁₋₅ saturated hydrocarbyl, cyano, CONH₂, CONHR⁹, CF₃, NH₂, NHCOR⁹ or NHCONHR⁹; R⁵ and R⁷ are each independently selected from hydrogen, halogen, C₁₋₅ saturated hydrocarbyl, cyano and CF₃; R⁹ is phenyl or benzyl each optionally substituted by one or substituents selected from halogen, hydroxy, trifluoromethyl, cyano, nitro, carboxy, amino, mono- or di-C₁₋₄ hydrocarbylamino; a group R^(a)-R^(b) wherein R^(a) is a bond, O, CO, X¹C(X²), C(X²)X¹, X¹C(X²)X¹, S, SO, SO₂, NR^(c), SO₂NR^(c) or NR^(c)SO₂; and R^(b) is selected from hydrogen, heterocyclic groups having from 3 to 12 ring members, and a C₁₋₈ hydrocarbyl group optionally substituted by one or more substituents selected from hydroxy, oxo, halogen, cyano, nitro, carboxy, amino, mono- or di-C₁₋₄ hydrocarbylamino, carbocyclic and heterocyclic groups having from 3 to 12 ring members and wherein one or more carbon atoms of the C₁₋₈ hydrocarbyl group may optionally be replaced by O, S, SO, SO₂, NR^(c), X¹C(X²), C(X²)X¹ or X¹C(X²)X¹; R^(c) is selected from hydrogen and C₁₋₄ hydrocarbyl; and X¹ is O, S or NR^(c) and X² is ═O, ═S or ═NR^(c).
 111. A compound according to claim 109 having the formula (II):

or a salt, solvate tautomer or N-oxide thereof; wherein R¹, R⁴, Q¹, Q², T, J¹, J² and G are as defined in claim
 109. 112. A compound according to claim 111 of the formula (IIa):

or a salt, solvate tautomer or N-oxide thereof; wherein R¹ is an aryl or heteroaryl group; G is selected from NR²R³, OH and SH; and R⁴, Q¹, Q², T, J¹ and J² are as defined in claim
 6. 113. A compound according to claim 109 wherein T is N or CH.
 114. A compound according to claim 109 wherein J¹-J² is selected from N═CH, HC═N, HC═CH and HN—C(O).
 115. A compound according to claim 109 wherein each of R⁶, R⁷ and R⁸ when present is hydrogen.
 116. A compound according to claim 109 wherein G is NR²R³ and R² and R³ are independently selected from hydrogen, C₁₋₄ hydrocarbyl and C₁₋₄ acyl.
 117. A compound according to claim 116 wherein NR²R³ is an amino group or a methylamino group.
 118. A compound according to claim 109 wherein R¹ is an aryl or heteroaryl group which is unsubstituted or is substituted by one or more substituents R¹⁰ selected from halogen, hydroxy, trifluoromethyl, cyano, nitro, carboxy, amino, mono- or di-C₁₋₄ hydrocarbylamino, carbocyclic and heterocyclic groups having from 3 to 12 ring members; a group R^(a)-R^(b) wherein R^(a) is a bond, O, CO, X¹C(X²), C(X²)X¹, X¹C(X²)X¹, S, SO, SO₂, NR^(c), SO₂NR^(c) or NR^(c)SO₂; and R^(b) is selected from hydrogen, carbocyclic and heterocyclic groups having from 3 to 12 ring members, and a C₁₋₈ hydrocarbyl group optionally substituted by one or more substituents selected from hydroxy, oxo, halogen, cyano, nitro, carboxy, amino, mono- or di-C₁₋₄ hydrocarbylamino, carbocyclic and heterocyclic groups having from 3 to 12 ring members and wherein one or more carbon atoms of the C₁₋₈ hydrocarbyl group may optionally be replaced by O, S, SO, SO₂, NR^(c), X¹C(X²), C(X²)X¹ or X¹C(X²)X¹; R^(c) is selected from hydrogen and C₁₋₄ hydrocarbyl; and X¹ is O, S or NR^(c) and X² is ═O, ═S or ═NR^(c).
 119. A compound according to claim 118 wherein the aryl or heteroaryl group is substituted by one or more substituents R^(10c) selected from: halogen, hydroxy, trifluoromethyl, cyano, amino, mono- or di-C₁₋₄ alkylamino, cyclopropylamino, monocyclic carbocyclic and heterocyclic groups having from 3 to 7 ring members of which 0, 1 or 2 are selected from O, N and S and the remainder are carbon atoms, wherein the monocyclic carbocyclic and heterocyclic groups are optionally substituted by one or more substituents selected from halogen, hydroxy, trifluoromethyl, cyano and methoxy; a group R^(a)-R^(b); R^(a) is a bond, O, CO, OC(O), NR^(c)C(O), OC(NR^(c)), C(O)O, C(O)NR^(c), S, SO, SO₂, NR^(c), SO₂NR^(c) or NR^(c)SO₂; R^(b) is selected from hydrogen, monocyclic carbocyclic and heterocyclic groups having from 3 to 7 ring members of which 0, 1 or 2 are selected from O, N and S and the remainder are carbon atoms, wherein the monocyclic carbocyclic and

where (X) and (XI) may be suitably protected and wherein T, J¹, J², Q¹, Q², G, E, and R¹ to R⁵ are as defined in any one of the preceding claims, one of the groups X and Y is chlorine, bromine or iodine or a trifluoromethane-sulphonate (triflate) group, and the other one of the groups X and Y is a boronate residue, for example a boronate ester or boronic acid residue; in the presence of a palladium catalyst; or (ii) when E is a non-aromatic cyclic group and is linked to the bicyclic group by a nitrogen atom, the reaction of a compound of the formula (XVI) where T is N, with a compound of the formula (XVII) or a protected derivative thereof:

where R¹, Q¹, Q² and G are as defined in any one of the preceding claims and the ring E represents a cyclic group E containing a nucleophilic NH group as a ring member. heterocyclic groups are optionally substituted by one or more substituents selected from halogen, hydroxy, trifluoromethyl, cyano and methoxy; and R^(b) is further selected from a C₁₋₈ hydrocarbyl group optionally substituted by one or more substituents selected from hydroxy, oxo, halogen, cyano, amino, mono- or di-C₁₋₄ alkylamino, monocyclic carbocyclic and heterocyclic groups having from 3 to 7 ring members of which 0, 1 or 2 are selected from O, N and S and the remainder are carbon atoms, wherein the monocyclic carbocyclic and heterocyclic groups are optionally substituted by one or more substituents selected from halogen, hydroxy, trifluoromethyl, cyano and methoxy, and wherein one or two carbon atoms of the C₁₋₈ hydrocarbyl group may optionally be replaced by O, S or NR^(c); provided that R^(a) is not a bond when R^(b) is hydrogen; and R^(c)C is selected from hydrogen and C₁₋₄ alkyl.
 120. A compound according to claim 109 wherein R¹ is a phenyl group which is unsubstituted or substituted by up to 5 substituents selected from hydroxy; C₁₋₄ acyloxy; fluorine; chlorine; bromine; trifluoromethyl; trifluoromethoxy; difluoromethoxy; benzyloxy; cyano; C₁₋₄ hydrocarbyloxy and C₁₋₄ hydrocarbyl each optionally substituted by C₁₋₂ alkoxy or hydroxy.
 121. A compound according to claim 112, having the formula (IV):

wherein m is 0, 1 or 2; m′ is 0 or 1 provided that the sum of m and m′ is in the range 0 to 2; n is 0 or 1; p is 0, 1, 2 or 3; R^(x) and R^(y) are the same or different and each is selected from hydrogen, methyl and fluorine; R¹² is CN or NR²R³; J¹, J², T, R², R³, R⁴, are as defined in claim 112; and each R¹³ is independently selected from R¹⁰, R^(10a), R^(10b) and R^(10c); wherein R¹⁰ is selected from: halogen, hydroxy, trifluoromethyl, cyano, nitro, carboxy, amino, mono- or di-C₁₋₄ hydrocarbylamino, carbocyclic and heterocyclic groups having from 3 to 12 ring members; a group R^(a)-R^(b) wherein R^(a) is a bond, O, CO, X¹C(X²), C(X²)X¹, X¹C(X²)X¹, S, SO, SO₂, NR^(c), SO₂NR^(c) or NR^(c)SO₂; and R^(b) is selected from hydrogen, carbocyclic and heterocyclic groups having from 3 to 12 ring members, and a C₁₋₈ hydrocarbyl group optionally substituted by one or more substituents selected from hydroxy, oxo, halogen, cyano, nitro, carboxy, amino, mono- or di-C₁₋₄ hydrocarbylamino, carbocyclic and heterocyclic groups having from 3 to 12 ring members and wherein one or more carbon atoms of the C₁₋₈ hydrocarbyl group may optionally be replaced by O, S, SO, SO₂, NR^(c), X¹C(X²), C(X²)X¹ or X¹C(X²)X¹; R^(c) is selected from hydrogen and C₁₋₄ hydrocarbyl; and X¹ is O, S or NR^(c) and X² is ═O, ═S or ═NR^(c); R^(10a) is selected from: halogen, hydroxy, trifluoromethyl, cyano, nitro, carboxy, amino, mono- or di-C₁₋₄ hydrocarbylamino, carbocyclic and heterocyclic groups having from 3 to 7 ring members; a group R^(a)-R^(b) wherein R^(a) is a bond, O, CO, OC(O), NR^(c)C(O), OC(NR^(c)), C(O)O, C(O)NR^(c), OC(O)O, NR^(c)C(O)O, OC(O)NR^(c), NR^(c)C(O)NR^(c), S, SO, SO₂, NR^(c), SO₂NR^(c) or NR^(c)SO₂; and R^(b) is selected from hydrogen, carbocyclic and heterocyclic groups having from 3 to 7 ring members, and a C₁₋₈ hydrocarbyl group optionally substituted by one or more substituents selected from hydroxy, oxo, halogen, cyano, nitro, carboxy, amino, mono- or di-C₁₋₄ hydrocarbylamino, carbocyclic and heterocyclic groups having from 3 to 7 ring members and wherein one or more carbon atoms of the C₁₋₈ hydrocarbyl group may optionally be replaced by O, S, SO, SO₂, NR^(c), OC(O), NR^(c)C(O), OC(NR^(c)), C(O)O, C(O)NR^(c), OC(O)O, NR^(c)C(O)O, OC(O)NR^(c) or NR^(c)C(O)NR^(c); R^(c) is selected from hydrogen and C₁₋₄ hydrocarbyl; R^(10b) is selected from: halogen, hydroxy, trifluoromethyl, cyano, amino, mono- or di-C₁₋₄ alkylamino, cyclopropylamino, carbocyclic and heterocyclic groups having from 3 to 7 ring members; a group R^(a)-R^(b) wherein R^(a) is a bond, O, CO, OC(O), NR^(c)C(O), OC(NR^(c)), C(O)O, C(O)NR^(c), S, SO, SO₂, NR^(c), SO₂NR^(c) or NR^(c)SO₂; and R^(b) is selected from hydrogen, carbocyclic and heterocyclic groups having from 3 to 7 ring members, and a C₁₋₈ hydrocarbyl group optionally substituted by one or more substituents selected from hydroxy, oxo, halogen, cyano, amino, mono- or di-C₁₋₄ alkylamino, carbocyclic and heterocyclic groups having from 3 to 7 ring members and wherein one or more carbon atoms of the C₁₋₈ hydrocarbyl group may optionally be replaced by O, S, SO, SO₂ or NR^(c); provided that R^(a) is not a bond when R^(b) is hydrogen; and R^(c) is selected from hydrogen and C₁₋₄ alkyl. R^(10c) is selected from: halogen, hydroxy, trifluoromethyl, cyano, amino, mono- or di-C₁₋₄ alkylamino, cyclopropylamino, monocyclic carbocyclic and heterocyclic groups having from 3 to 7 ring members of which 0, 1 or 2 are selected from O, N and S and the remainder are carbon atoms, wherein the monocyclic carbocyclic and heterocyclic groups are optionally substituted by one or more substituents selected from halogen, hydroxy, trifluoromethyl, cyano and methoxy; a group R^(a)-R^(b); R^(a) is a bond, O, CO, OC(O), NR^(c)C(O), OC(NR^(c)), C(O)O, C(O)NR^(c), S, SO, SO₂, NR^(c), SO₂NR^(c) or NR^(c)SO₂; R^(b) is selected from hydrogen, monocyclic carbocyclic and heterocyclic groups having from 3 to 7 ring members of which 0, 1 or 2 are selected from O, N and S and the remainder are carbon atoms, wherein the monocyclic carbocyclic and heterocyclic groups are optionally substituted by one or more substituents selected from halogen, hydroxy, trifluoromethyl, cyano and methoxy; and R^(b) is further selected from a C₁₋₈ hydrocarbyl group optionally substituted by one or more substituents selected from hydroxy, oxo, halogen, cyano, amino, mono- or di-C₁₋₄ alkylamino, monocyclic carbocyclic and heterocyclic groups having from 3 to 7 ring members of which 0, 1 or 2 are selected from O, N and S and the remainder are carbon atoms, wherein the monocyclic carbocyclic and heterocyclic groups are optionally substituted by one or more substituents selected from halogen, hydroxy, trifluoromethyl, cyano and methoxy, and wherein one or two carbon atoms of the C₁₋₈ hydrocarbyl group may optionally be replaced by O, S or NR^(c); provided that R^(a) is not a bond when R^(b) is hydrogen; and R^(c) is selected from hydrogen and C₁₋₄ alkyl.
 122. A compound according to claim 121 wherein m is 0 or
 1. 123. A compound according to claim 121 wherein R¹² is selected from NH₂, NHMe and NMe₂
 124. A compound according to claim 121 of the formula (V):

or a salt, solvate, tautomer or N-oxide thereof, wherein R^(10c) is selected from: halogen, hydroxy, trifluoromethyl, cyano, amino, mono- or di-C₁₋₄ alkylamino, cyclopropylamino, monocyclic carbocyclic and heterocyclic groups having from 3 to 7 ring members of which 0, 1 or 2 are selected from O, N and S and the remainder are carbon atoms, wherein the monocyclic carbocyclic and heterocyclic groups are optionally substituted by one or more substituents selected from halogen, hydroxy, trifluoromethyl, cyano and methoxy; a group R^(a)-R^(b); R^(a) is a bond, O, CO, OC(O), NR^(c)C(O), OC(NR^(c)), C(O)O, C(O)NR^(c), S, SO, SO₂, NR^(c), SO₂NR^(c) or NR^(c)SO₂; R^(b) is selected from hydrogen, monocyclic carbocyclic and heterocyclic groups having from 3 to 7 ring members of which 0, 1 or 2 are selected from O, N and S and the remainder are carbon atoms, wherein the monocyclic carbocyclic and heterocyclic groups are optionally substituted by one or more substituents selected from halogen, hydroxy, trifluoromethyl, cyano and methoxy; and R^(b) is further selected from a C₁₋₈ hydrocarbyl group optionally substituted by one or more substituents selected from hydroxy, oxo, halogen, cyano, amino, mono- or di-C₁₋₄ alkylamino, monocyclic carbocyclic and heterocyclic groups having from 3 to 7 ring members of which 0, 1 or 2 are selected from O, N and S and the remainder are carbon atoms, wherein the monocyclic carbocyclic and heterocyclic groups are optionally substituted by one or more substituents selected from halogen, hydroxy, trifluoromethyl, cyano and methoxy, and wherein one or two carbon atoms of the C₁₋₈ hydrocarbyl group may optionally be replaced by O, S or NR^(c); provided that R^(a) is not a bond when R^(b) is hydrogen; and R^(c) is selected from hydrogen and C₁₋₄ alkyl; p is 1, 2 or 3; R^(w) is hydrogen or methyl; R^(x) and R^(y) are the same or different and each is selected from hydrogen, methyl and fluorine; and J¹, J² and R⁴ are as defined in claim
 109. 125. A compound according to claim 112 of the formula (VI):

wherein R^(q) is hydrogen or methyl.
 126. A compound according to claim 109 of the formula (VII):

wherein Ar is a 5- or 6-membered monocyclic aryl or heteroaryl group having up to 2 heteroatom ring members selected from O, N and S and being optionally substituted by one or two substituents selected from fluorine, chlorine, methyl and methoxy; R^(10d) is a substituent selected from fluorine, chlorine, methyl, trifluoromethyl, trifluoromethoxy and methoxy; r is 0, 1 or 2; and T, Q¹, Q², NR²R¹, R⁴, and J¹-J² are as defined in claim
 109. 127. A compound according to claim 126 wherein Ar is unsubstituted phenyl.
 128. A compound as defined in claim 109 in the form of a salt, solvate or N-oxide.
 129. A method of inhibiting protein kinase B or protein kinase A, which method comprises contacting the kinase with a kinase-inhibiting compound as defined in claim
 109. 130. A method of modulating a cellular process by inhibiting the activity of a protein kinase B or protein kinase A using a compound as defined in claim
 109. 131. A pharmaceutical composition comprising a compound as defined in claim 109 and a pharmaceutically acceptable carrier.
 132. A method for the diagnosis and treatment of a disease state or condition mediated by protein kinase B or protein kinase A, which method comprises (i) screening a patient to determine whether a disease or condition from which the patient is or may be suffering is one which would be susceptible to treatment with a compound having activity against protein kinase B or protein kinase A; and (ii) where it is indicated that the disease or condition from which the patient is thus susceptible, thereafter administering to the patient a compound as defined in claim
 109. 133. A process for the preparation of a compound as defined in claim 109, which process comprises: (i) when E is an aryl or heteroaryl group, the reaction of a compound of the formula (X) with a compound of the formula (XI):

where (X) and (XI) may be suitably protected and wherein T, J¹, J², Q¹, Q², G, E, and R¹ to R⁵ are as defined in any one of the preceding claims, one of the groups X and Y is chlorine, bromine or iodine or a trifluoromethane-sulphonate (triflate) group, and the other one of the groups X and Y is a boronate residue, for example a boronate ester or boronic acid residue; in the presence of a palladium catalyst; or (ii) when E is a non-aromatic cyclic group and is linked to the bicyclic group by a nitrogen atom, the reaction of a compound of the formula (XVI) where T is N, with a compound of the formula (XVII) or a protected derivative thereof:

where R¹, Q¹, Q² and G are as defined in any one of the preceding claims and the ring E represents a cyclic group E containing a nucleophilic NH group as a ring member. 